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Hyeraci M, Papanikolau ES, Grimaldi M, Ricci F, Pallotta S, Monetta R, Minafò YA, Di Lella G, Galdo G, Abeni D, Fania L, Dellambra E. Systemic Photoprotection in Melanoma and Non-Melanoma Skin Cancer. Biomolecules 2023; 13:1067. [PMID: 37509103 PMCID: PMC10377635 DOI: 10.3390/biom13071067] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK), are the most common cancer diseases in the Caucasian race. If diagnosed late and improperly treated, BCC and SCC can become locally advanced and metastasize. Malignant melanoma (MM) is less frequent but more lethal than NMSC. Given the individual and social burdens of skin cancers, performing an adequate prevention is needed. Ultraviolet (UV) ray exposure is one of the main risk factors for skin cancer. Thus, the first-choice prevention strategy is represented by photoprotection that can be both topical and systemic. The latter consists of the oral administration of molecules which protect human skin against the damaging effects of UV rays, acting through antioxidant, anti-inflammatory, or immunomodulator mechanisms. Although several compounds are commonly used for photoprotection, only a few molecules have demonstrated their effectiveness in clinical trials and have been included in international guidelines for NMSC prevention (i.e., nicotinamide and retinoids). Moreover, none of them have been demonstrated as able to prevent MM. Clinical and preclinical data regarding the most common compounds used for systemic photoprotection are reported in this review, with a focus on the main mechanisms involved in their photoprotective properties.
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Affiliation(s)
- Mariafrancesca Hyeraci
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131Padua, Italy
| | | | - Marta Grimaldi
- Department of Medical and Surgical Sciences, Division of Dermatology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Ricci
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Sabatino Pallotta
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Rosanna Monetta
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Ylenia Aura Minafò
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Giovanni Di Lella
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Giovanna Galdo
- Dermatology Unit, AORN San Giuseppe Moscati, 83100 Avellino, Italy
| | - Damiano Abeni
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Luca Fania
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
| | - Elena Dellambra
- IDI-IRCCS, Dermatological Research Hospital, Via dei Monti di Creta 104, 00167 Rome, Italy
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Monroy D, Serrano A, Galor A, Karp CL. Medical treatment for ocular surface squamous neoplasia. Eye (Lond) 2023; 37:885-893. [PMID: 36754986 PMCID: PMC10050251 DOI: 10.1038/s41433-023-02434-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 12/17/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
Ocular surface squamous neoplasia (OSSN) is the most common non-melanocytic tumour of the ocular surface. Surgical excision with wide margins using the "no-touch" method was originally the most popular treatment for OSSN. However, in the past two decades, the use of topical medications for OSSN treatment has gained a reputation amongst ophthalmologists for being an effective alternative to surgical excision. Furthermore, technological advancements, such as those seen in high-resolution optical coherence tomography (HR-OCT) for the anterior segment, have facilitated the diagnosis and monitoring of OSSN. When selecting a topical agent, interferon alpha-2b (IFNα-2b) and 5-fluorouracil (5-FU) are two of the gentlest medications used for OSSN and are often considered first line therapies due to their high-resolution rates and mild side effect profiles. Mitomycin C (MMC), on the other hand, has a highly toxic profile; therefore, while effective, in our hands it is considered as a second-line treatment for OSSN if the other modalities fail. In addition, newer and less studied agents, such as immune checkpoint inhibitors, retinoic acid, aloe vera, and anti-vascular endothelial growth factor have anti-neoplastic properties and have shown potential for the treatment of OSSN. We enclose an updated literature review of medical treatments for OSSN.
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Grants
- R01 EY026174 NEI NIH HHS
- P30 EY014801 NEI NIH HHS
- I01 BX004893 BLRD VA
- R61 EY032468 NEI NIH HHS
- I01 CX002015 CSRD VA
- The Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences R&D (CSRD) I01 CX002015 (Dr. Galor) and Biomedical Laboratory R&D (BLRD) Service I01 BX004893 (Dr. Galor), Department of Defense Gulf War Illness Research Program (GWIRP) W81XWH-20-1-0579 (Dr. Galor) and Vision Research Program (VRP) W81XWH-20-1-0820 (Dr. Galor), National Eye Institute R01EY026174 (Dr. Galor) and R61EY032468 (Dr. Galor), and Research to Prevent Blindness Unrestricted Grant (institutional).
- NIH Center Core Grant P30EY014801, RPB Unrestricted Award, Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Robert Farr Family Grant, The Grant and Diana Stanton-Thornbrough Grant,The Robert Baer Family Grant, The Roberto and Antonia Menendez Grant, The Emilyn Page and Mark Feldberg Grant, The Calvin and Flavia Oak Support Fund, The Robert Farr Family Grant, The Jose Ferreira de Melo Grant, The Richard and Kathy Lesser Grant, The Honorable A. Jay Cristol Grant, The Michele and Ted Kaplan Grant, The Carol Soffer Grant, and the Richard Azar Family Grant(institutional grants).
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Affiliation(s)
- David Monroy
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andres Serrano
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA
| | - Anat Galor
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Ophthalmology, Miami Veterans Administration Medical Center, Miami, FL, USA
| | - Carol L Karp
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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Sun MH, Gong TT, Xu HL, Yin JL, Yang HJ, Zou BJ, Chen HY, Du ZD, Wang R, Yan S, Xu J, Liu FH, Sun ML, Gao S, Zhao YH, Wu QJ. Association between pre-diagnostic dietary antioxidant vitamin consumption and ovarian cancer survival: a prospective cohort study. Food Funct 2023; 14:911-920. [PMID: 36537732 DOI: 10.1039/d2fo03213a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background: Epidemiological evidence regarding the relationship between dietary antioxidant vitamin intake and ovarian cancer (OC) survival is not clear. Herein, we aimed to first evaluate this topic in a prospective cohort study in China. Methods: The present study included participants from the Ovarian Cancer Follow-Up Study, which was a hospital-based prospective cohort study including OC patients who were aged 18 to 79 years during 2015-2020. The information on the intake of antioxidant vitamins, consisting of vitamin A, retinol, α-carotene, β-carotene, vitamin C, and vitamin E, and other diet information was obtained through a 111-item food frequency questionnaire. Deaths were recorded until March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival were evaluated using Cox proportional hazards models. Results: There were 130 (18.49%) deaths among 703 OC patients during a median 37.19 months follow-up. In the multivariable-adjusted model, the highest tertile of dietary vitamin C (HR = 0.43, 95% CI = 0.25-0.75, P for trend <0.05) and β-carotene intake (HR = 0.52, 95% CI = 0.31-0.87, P for trend <0.05) was inversely associated with the overall survival of OC when compared with the lowest tertile group. Retinol, vitamin A, vitamin E, and α-carotene consumption showed no association with OC survival. Of note is that the multiplicative interaction was identified between vitamin C intake and residual lesions in OC survival (P for interaction <0.05). Conclusion: Our findings indicate that pre-diagnostic higher vitamin C and β-carotene intake was associated with improved OC survival.
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Affiliation(s)
- Ming-Hui Sun
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ting-Ting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - He-Li Xu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jia-Li Yin
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hui-Juan Yang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bing-Jie Zou
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hong-Yu Chen
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zong-Da Du
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ran Wang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shi Yan
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jin Xu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fang-Hua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ming-Li Sun
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Song Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Hong Zhao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi-Jun Wu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China. .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China. .,Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China.,Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Reproductive and Genetic Medicine (China Medical University), National Health Commission, Shenyang, China
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Hirota A, Clément JE, Tanikawa S, Nonoyama T, Komatsuzaki T, Gong JP, Tanaka S, Imajo M. ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14235890. [PMID: 36497371 PMCID: PMC9739577 DOI: 10.3390/cancers14235890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/18/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.
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Affiliation(s)
- Akira Hirota
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Jean-Emmanuel Clément
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Satoshi Tanikawa
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
| | - Takayuki Nonoyama
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Tamiki Komatsuzaki
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Research Center of Mathematics for Social Creativity, Research Institute for Electronic Science, Hokkaido University, Sapporo 001-0020, Japan
| | - Jian Ping Gong
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan
| | - Shinya Tanaka
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masamichi Imajo
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
- Correspondence: ; Tel.: +81-11-706-9683
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Kulkarni NV, Shetty RA, Kumari N S, Shetty VV, Krishna R, Arumugam M, Kalal AA, Shetty P. Correlation of preferentially expressed antigen of melanoma (PRAME) gene expression with clinical characteristics in acute leukemia patients. J Genet Eng Biotechnol 2022; 20:97. [PMID: 35788450 PMCID: PMC9256891 DOI: 10.1186/s43141-022-00376-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/02/2022] [Indexed: 11/13/2022]
Abstract
Background Preferentially expressed antigen of melanoma (PRAME) gene is regularly overexpressed in acute leukemia (AL) and other malignant diseases which are recognized by human leucocyte antigen (HLA-24) located in the human chromosome of 22q11 coded by 509 amino acids. To rule out the PRAME gene expression in AL patients and its correlation with clinical characteristics in the Indian population set up by RT-qPCR. Results A total of 42 samples collected, 29 (69.4%) were males, and 13 (30.95%) were females, with a mean and standard deviation for age were 39.07 ± 22.22 years. Of which AML were of 22 (52.38%) cases, ALL were of 14 (33.33%) cases, and 6 (14.2%) cases which included other forms of leukemia. PRAME gene expression was highly expressed in thirty-three 27 (64.28%) AL patients compared to the least expression in healthy individuals. No significant difference between the different forms of AL (p=0.3203) was observed. Cytogenetic analysis of normal karyotype (NK), abnormal karyotype (Ab. K), and culture failure (CF) displayed statistical non-significance (p=0.5801). Among cytogenetic abnormalities obtained, no significant differences between the groups were observed (p=0.8507). Chloride, potassium, and absolute lymphocyte count (ALC) was found to be statistically significant with p=0.0038**, p=0.0358*, and p=0.0216*, respectively, between all other clinical characteristics. There was no correlation between the PRAME gene expression and clinical parameters. Conclusion PRAME gene expression in AL patients was highly expressed, comparable to studies reported globally with significant cytogenetic results. PRAME gene could be used as a potential diagnostic marker for monitoring the malignancies and minimal residual disease in AL.
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Affiliation(s)
- Nagaraj V Kulkarni
- Central Research Laboratory, KSHEMA Centre for Genetic Services, KS Hegde Medical Academy, NITTE (Deemed to be) University, Derlakatte, Mangalore, Karnataka, 575 018, India
| | - Reshma A Shetty
- Central Research Laboratory, KSHEMA Centre for Genetic Services, KS Hegde Medical Academy, NITTE (Deemed to be) University, Derlakatte, Mangalore, Karnataka, 575 018, India
| | - Suchetha Kumari N
- Department of Biochemistry, KS Hegde Medical Academy, NITTE (Deemed to be) University, Nityanandanagar, Deralakatte, Mangalore, Karnataka, 575 018, India
| | - Vijith V Shetty
- Department of Medical Oncology, KS Hegde Medical Academy, NITTE (Deemed to be University), Derlakatte, Mangalore, Karnataka, 575 018, India
| | - Rajesh Krishna
- Yenepoya Medical College Hospital, Yenepoya (Deemed to be) University, Nityanandanagar, Deralakatte, Mangalore, Karnataka, 575 018, India
| | - Meenakshi Arumugam
- Central Research Laboratory, KSHEMA Centre for Genetic Services, KS Hegde Medical Academy, NITTE (Deemed to be) University, Derlakatte, Mangalore, Karnataka, 575 018, India
| | - Akanksha A Kalal
- Central Research Laboratory, KSHEMA Centre for Genetic Services, KS Hegde Medical Academy, NITTE (Deemed to be) University, Derlakatte, Mangalore, Karnataka, 575 018, India
| | - Prashanth Shetty
- Central Research Laboratory, KSHEMA Centre for Genetic Services, KS Hegde Medical Academy, NITTE (Deemed to be) University, Derlakatte, Mangalore, Karnataka, 575 018, India.
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Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects. Pharmaceuticals (Basel) 2022; 15:ph15050624. [PMID: 35631448 PMCID: PMC9145966 DOI: 10.3390/ph15050624] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 01/27/2023] Open
Abstract
Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.
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Lampis S, Raieli S, Montemurro L, Bartolucci D, Amadesi C, Bortolotti S, Angelucci S, Scardovi AL, Nieddu G, Cerisoli L, Paganelli F, Valente S, Fischer M, Martelli AM, Pasquinelli G, Pession A, Hrelia P, Tonelli R. The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma. J Exp Clin Cancer Res 2022; 41:160. [PMID: 35490242 PMCID: PMC9055702 DOI: 10.1186/s13046-022-02367-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/18/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Neuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB. METHODS By molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB. RESULTS We found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival. CONCLUSION Taken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB.
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Affiliation(s)
| | | | - Luca Montemurro
- Pediatric Unit, S. Orsola IRCCS, University of Bologna, Bologna, Italy
| | | | | | | | | | | | | | | | - Francesca Paganelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Bologna, Italy
| | - Sabrina Valente
- Biotechnology and Methods in Laboratory Medicine, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Matthias Fischer
- Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany; and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | | | - Gianandrea Pasquinelli
- Biotechnology and Methods in Laboratory Medicine, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Subcellular nephro-vascular diagnostic program, Pathology Unit S. Orsola IRCCS, University of Bologna, Bologna, Italy
| | - Andrea Pession
- Pediatric Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Roberto Tonelli
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
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8
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Neijenhuis LKA, de Myunck LDAN, Bijlstra OD, Kuppen PJK, Hilling DE, Borm FJ, Cohen D, Mieog JSD, Steup WH, Braun J, Burggraaf J, Vahrmeijer AL, Hutteman M. Near-Infrared Fluorescence Tumor-Targeted Imaging in Lung Cancer: A Systematic Review. Life (Basel) 2022; 12:life12030446. [PMID: 35330197 PMCID: PMC8950608 DOI: 10.3390/life12030446] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the most common cancer type worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype. Non-disseminated NSCLC is mainly treated with surgical resection. The intraoperative detection of lung cancer can be challenging, since small and deeply located pulmonary nodules can be invisible under white light. Due to the increasing use of minimally invasive surgical techniques, tactile information is often reduced. Therefore, several intraoperative imaging techniques have been tested to localize pulmonary nodules, of which near-infrared (NIR) fluorescence is an emerging modality. In this systematic review, the available literature on fluorescence imaging of lung cancers is presented, which shows that NIR fluorescence-guided lung surgery has the potential to identify the tumor during surgery, detect additional lesions and prevent tumor-positive resection margins.
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Affiliation(s)
- Lisanne K. A. Neijenhuis
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
- Centre for Human Drug Research, 2333 CL Leiden, The Netherlands;
| | - Lysanne D. A. N. de Myunck
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
| | - Okker D. Bijlstra
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
| | - Denise E. Hilling
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
- Department of Surgery, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Frank J. Borm
- Department of Pulmonology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Danielle Cohen
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - J. Sven D. Mieog
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
| | - Willem H. Steup
- Department of Surgery, HAGA Hospital, 2545 AA The Hague, The Netherlands;
| | - Jerry Braun
- Department of Cardiothoracic Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | | | - Alexander L. Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
| | - Merlijn Hutteman
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.K.A.N.); (L.D.A.N.d.M.); (O.D.B.); (P.J.K.K.); (D.E.H.); (J.S.D.M.); (A.L.V.)
- Department of Cardiothoracic Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Correspondence: ; Tel.: +31-71-526-51-00
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9
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Kazim N, Yen A. Evidence of off-target effects of bosutinib that promote retinoic acid-induced differentiation of non-APL AML cells. Cell Cycle 2021; 20:2638-2651. [PMID: 34836491 DOI: 10.1080/15384101.2021.2005275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
In the present study, we determined the effects of the Src family kinase (SFK) inhibitor, Bosutinib, and the engineered loss of the Lyn SFK on all-trans retinoic acid-induced leukemic cell differentiation. Retinoic acid (RA) is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing differentiation of a non-APL AML cell model, the HL-60 human myeloblastic (FAB-M2) leukemia cell line, via activation of a novel signalsome containing an ensemble of signaling molecules that drive differentiation. Bosutinib is an inhibitor of SFKs used to treat myeloid leukemias where prominent high expression of SFKs, in particular Lyn, has been observed. Using either Bosutinib or loss of Lyn expression due to shRNA promoted RA-induced phenotypic differentiation, G0 arrest, and respiratory burst (functional differentiation) of HL-60 cells. Signaling events putatively seminal to RA-induced differentiation, the expression of Fgr, Cbl, Slp-76 and Vav, and the phosphorylation of c-Raf (pS259), Vav (p-tyr), and Slp76 (p-tyr) were not inhibited by Bosutinib or loss of Lyn. Nor was RA-induced upregulation of p-tyr phosphorylation of p47phox, a member of the NADPH complex that produces ROS, a putative phosphorylation dependent signaling regulator. Surprisingly, Bosutinib still works in the absence of Lyn to enhance RA-induced differentiation and neither compromised RA-induced expression, nor phosphorylation of signaling molecules that drive differentiation. These findings suggested there is a novel, off-target, Lyn-independent effect of Bosutinib that is of therapeutic significance to differentiation therapy.
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Affiliation(s)
- Noor Kazim
- Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Andrew Yen
- Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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10
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The unfolding role of ceramide in coordinating retinoid-based cancer therapy. Biochem J 2021; 478:3621-3642. [PMID: 34648006 DOI: 10.1042/bcj20210368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/30/2022]
Abstract
Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.
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11
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Kim JA, Jang JH, Lee SY. An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications. Nutrients 2021; 13:3162. [PMID: 34579037 PMCID: PMC8465379 DOI: 10.3390/nu13093162] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/28/2021] [Accepted: 09/06/2021] [Indexed: 12/11/2022] Open
Abstract
Vitamin A and carotenoids are fat-soluble micronutrients that play important role as powerful antioxidants modulating oxidative stress and cancer development. Breast cancer is the most common malignancy in women. As the risk of breast cancer is dependent on various lifestyle factors such as dietary modifications, there is increasing interest surrounding the anti-cancerous properties of vitamin A and carotenoids. Despite the suggested protective roles of vitamin A and carotenoids in breast cancer development, their clinical application for the prevention and treatment of breast cancer is limited. In this narrative review, we discuss the roles of vitamin A and carotenoids along with the evaluation method of vitamin A status. We also exhibit the association of genetic variations involved in metabolism of vitamin A and carotenoids with cancers and other diseases. We demonstrate the epidemiological evidence for the relationship of vitamin A and carotenoids with breast cancer risk, their effects on cancer mechanism, and the recent updates in clinical practice of vitamin A or carotenoids as a potential therapeutic agent against breast cancer. This review provides insight into the preventive and therapeutic roles of vitamin A and carotenoids in breast cancer development and progression.
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Affiliation(s)
- Jee Ah Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; (J.A.K.); (J.-H.J.)
| | - Ja-Hyun Jang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; (J.A.K.); (J.-H.J.)
| | - Soo-Youn Lee
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea; (J.A.K.); (J.-H.J.)
- Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
- Department of Health Science and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, 115 Irwon-ro, Gangnam-gu, Seoul 06355, Korea
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12
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Alam W, Ullah H, Santarcangelo C, Di Minno A, Khan H, Daglia M, Arciola CR. Micronutrient Food Supplements in Patients with Gastro-Intestinal and Hepatic Cancers. Int J Mol Sci 2021; 22:8014. [PMID: 34360782 PMCID: PMC8347237 DOI: 10.3390/ijms22158014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 02/05/2023] Open
Abstract
Colorectal carcinogenesis is the second most common cause of mortality across all types of malignancies, followed by hepatic and stomach cancers. Chemotherapy and radiotherapy are key approaches to treating cancer patients, but these carry major concerns, such as a high risk of side effects, poor accessibility, and the non-selective nature of chemotherapeutics. A number of natural products have been identified as countering various forms of cancer with fewer side effects. The potential impact of vitamins and minerals on long-term health, cognition, healthy development, bone formation, and aging has been supported by experimental and epidemiological studies. Successful treatment may thus be highly influenced by the nutritional status of patients. An insufficient diet could lead to detrimental effects on immune status and tolerance to treatment, affecting the ability of chemotherapy to destroy cancerous cells. In recent decades, most cancer patients have been taking vitamins and minerals to improve standard therapy and/or to decrease the undesirable side effects of the treatment together with the underlying disease. On the other hand, taking dietary supplements during cancer therapy may affect the effectiveness of chemotherapy. Thus, micronutrients in complementary oncology must be selected appropriately and should be taken at the right time. Here, the potential impact of micronutrients on gastro-intestinal and hepatic cancers is explored and their molecular targets are laid down.
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Affiliation(s)
- Waqas Alam
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan; (W.A.); (H.K.)
| | - Hammad Ullah
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (C.S.); (A.D.M.)
| | - Cristina Santarcangelo
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (C.S.); (A.D.M.)
| | - Alessandro Di Minno
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (C.S.); (A.D.M.)
- CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan; (W.A.); (H.K.)
| | - Maria Daglia
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; (H.U.); (C.S.); (A.D.M.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - Carla Renata Arciola
- Laboratorio di Patologia delle Infezioni Associate all’Impianto, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 14, 40136 Bologna, Italy
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Hunsu VO, Facey COB, Fields JZ, Boman BM. Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies. Int J Mol Sci 2021; 22:7731. [PMID: 34299349 PMCID: PMC8304138 DOI: 10.3390/ijms22147731] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
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Affiliation(s)
- Victoria O. Hunsu
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
| | | | - Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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14
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O.B. Facey C, M. Boman B. Retinoids in Treatment of Colorectal Cancer. COLORECTAL CANCER 2021. [DOI: 10.5772/intechopen.93699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Retinoids are vitamin A metabolites best known for their role in embryonic development. Indeed, retinoid acid (RA) signaling plays a key role in regulating the development of the embryo body-plan by controlling embryonic stem cells (SCs). Retinoids function through their ability to induce cellular differentiation. Mutations in RA signaling pathway genes occur in most human cancers. The classic example is the chromosomal translocation involving RA receptor alpha in acute promyelocytic leukemia (APL). Because all-trans retinoic acid (ATRA) is a highly effective and often curative treatment for APL patients, determining if retinoids are efficacious for other cancer types is imperative. We review the current research on retinoids in colorectal cancer (CRC) and provide bioinformatics analyses of RA signaling. Our results show that most RA pathway genes are overexpressed and often mutated in CRC. Moreover, aberrant expression of many RA signaling proteins predicts decreased CRC patient survival. We also review aldehyde dehydrogenase (ALDH) expression in CRC because ALDH is a key enzyme in RA signaling, which regulates colonic SCs. Further investigation of RA signaling mechanisms that regulate colon SCs and how dysregulation contributes to the SC overpopulation that drives CRC growth should provide insight into strategies for designing new SC-targeted therapies for CRC.
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15
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Borges GSM, Lima FA, Carneiro G, Goulart GAC, Ferreira LAM. All-trans retinoic acid in anticancer therapy: how nanotechnology can enhance its efficacy and resolve its drawbacks. Expert Opin Drug Deliv 2021; 18:1335-1354. [PMID: 33896323 DOI: 10.1080/17425247.2021.1919619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: All-trans retinoic acid (ATRA, tretinoin) is the main drug used in the treatment of acute promyelocytic leukemia (APL). Despite its impressive activity against APL, the same could not be clinically observed in other types of cancer. Nanotechnology can be a tool to enhance ATRA anticancer efficacy and resolve its drawbacks in APL as well as in other malignancies.Areas covered: This review covers ATRA use in APL and non-APL cancers, the problems that were found in ATRA therapy and how nanoencapsulation can aid to circumvent them. Pre-clinical results obtained with nanoencapsulated ATRA are shown as well as the two ATRA products based on nanotechnology that were clinically tested: ATRA-IV® and Apealea®.Expert opinion: ATRA presents interesting properties to be used in anticancer therapy with a notorious differentiation and antimetastatic activity. Bioavailability and resistance limitations impair the use of ATRA in non-APL cancers. Nanotechnology can circumvent these issues and provide tools to enhance its anticancer activities, such as co-loading of multiple drug and active targeting to tumor site.
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Affiliation(s)
- Gabriel Silva Marques Borges
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Flávia Alves Lima
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Guilherme Carneiro
- Departamento De Farmácia, Faculdade De Ciências Biológicas E Da Saúde, Universidade Federal Dos Vales Do Jequitinhonha E Mucuri, Diamantina, Brazil
| | - Gisele Assis Castro Goulart
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
| | - Lucas Antônio Miranda Ferreira
- Departamento De Produtos Farmacêuticos, Faculdade De Farmácia, Universidade Federal De Minas Gerais, Belo Horizonte, Brazil
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16
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Carazo A, Macáková K, Matoušová K, Krčmová LK, Protti M, Mladěnka P. Vitamin A Update: Forms, Sources, Kinetics, Detection, Function, Deficiency, Therapeutic Use and Toxicity. Nutrients 2021; 13:1703. [PMID: 34069881 PMCID: PMC8157347 DOI: 10.3390/nu13051703] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin A is a group of vital micronutrients widely present in the human diet. Animal-based products are a rich source of the retinyl ester form of the vitamin, while vegetables and fruits contain carotenoids, most of which are provitamin A. Vitamin A plays a key role in the correct functioning of multiple physiological functions. The human organism can metabolize natural forms of vitamin A and provitamin A into biologically active forms (retinol, retinal, retinoic acid), which interact with multiple molecular targets, including nuclear receptors, opsin in the retina and, according to the latest research, also some enzymes. In this review, we aim to provide a complex view on the present knowledge about vitamin A ranging from its sources through its physiological functions to consequences of its deficiency and metabolic fate up to possible pharmacological administration and potential toxicity. Current analytical methods used for its detection in real samples are included as well.
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Affiliation(s)
- Alejandro Carazo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
| | - Kateřina Macáková
- Department of Pharmacognosy, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; (K.M.); (L.K.K.)
| | - Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; (K.M.); (L.K.K.)
- Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Michele Protti
- The Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum–University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
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17
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Everts HB, Akuailou EN. Retinoids in Cutaneous Squamous Cell Carcinoma. Nutrients 2021; 13:E153. [PMID: 33466372 PMCID: PMC7824907 DOI: 10.3390/nu13010153] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 02/07/2023] Open
Abstract
Animal studies as early as the 1920s suggested that vitamin A deficiency leads to squamous cell metaplasia in numerous epithelial tissues including the skin. However, humans usually die from vitamin A deficiency before cancers have time to develop. A recent long-term cohort study found that high dietary vitamin A reduced the risk of cutaneous squamous cell carcinoma (cSCC). cSCC is a form of nonmelanoma skin cancer that primarily occurs from excess exposure to ultraviolet light B (UVB). These cancers are expensive to treat and can lead to metastasis and death. Oral synthetic retinoids prevent the reoccurrence of cSCC, but side effects limit their use in chemoprevention. Several proteins involved in vitamin A metabolism and signaling are altered in cSCC, which may lead to retinoid resistance. The expression of vitamin A metabolism proteins may also have prognostic value. This article reviews what is known about natural and synthetic retinoids and their metabolism in cSCC.
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Affiliation(s)
- Helen B Everts
- Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX 76209, USA
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18
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Ortega MA, Fraile-Martínez O, García-Honduvilla N, Coca S, Álvarez-Mon M, Buján J, Teus MA. Update on uveal melanoma: Translational research from biology to clinical practice (Review). Int J Oncol 2020; 57:1262-1279. [PMID: 33173970 PMCID: PMC7646582 DOI: 10.3892/ijo.2020.5140] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Uveal melanoma is the most common type of intraocular cancer with a low mean annual incidence of 5‑10 cases per million. Tumours are located in the choroid (90%), ciliary body (6%) or iris (4%) and of 85% are primary tumours. As in cutaneous melanoma, tumours arise in melanocytes; however, the characteristics of uveal melanoma differ, accounting for 3‑5% of melanocytic cancers. Among the numerous risk factors are age, sex, genetic and phenotypic predisposition, the work environment and dermatological conditions. Management is usually multidisciplinary, including several specialists such as ophthalmologists, oncologists and maxillofacial surgeons, who participate in the diagnosis, treatment and complex follow‑up of these patients, without excluding the management of the immense emotional burden. Clinically, uveal melanoma generates symptoms that depend as much on the affected ocular globe site as on the tumour size. The anatomopathological study of uveal melanoma has recently benefited from developments in molecular biology. In effect, disease classification or staging according to molecular profile is proving useful for the assessment of this type of tumour. Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control. In the present study, the main epidemiological, clinical, physiopathological and molecular features of this disease are reviewed, and the associations among all these factors are discussed.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Oscar Fraile-Martínez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Santiago Coca
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
- Internal and Oncology Service (CIBER-EHD), University Hospital Príncipe de Asturias, Alcalá de Henares, 28805 Madrid
| | - Julia Buján
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid
- University Center for The Defense of Madrid (CUD-ACD), 28047 Madrid
| | - Miguel A. Teus
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28871 Madrid
- Ophthalmology Service, University Hospital Príncipe de Asturias, Alcalá de Henares, 28805 Madrid, Spain
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Jobani BM, Mohebi E, Najafzadeh N. In Vitro Anticancer Effects of All-trans Retinoic Acid in Combination with Dacarbazine against CD117+ Melanoma Cells. Drug Res (Stuttg) 2020; 70:563-569. [PMID: 33022719 DOI: 10.1055/a-1240-0072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Malignant melanoma is a common form of skin cancer that contains different cell types recognized by various cell surface markers. Dacarbazine-based combination chemotherapy is frequently used for the treatment of melanoma. Despite its potent anticancer properties, resistance to dacarbazine develops in malignant melanoma. Here, we aim to improve response to dacarbazine therapy by pretreatment with all-trans retinoic acid (ATRA) in CD117+ melanoma cells. METHODS The CD117+ melanoma cells were sorted from A375 malignant melanoma cell line using magnetic-activated cell sorting (MACS). The cell viability was examined by cell proliferation assay (MTT). Apoptosis was determined by acridine orange/ ethidium bromide staining. Indeed, we performed flow cytometry to evaluate the cell cycle arrest. RESULTS Here, the CD117+ melanoma cells were incubated with various concentrations of ATRA, dacarbazine, and their combination to determine IC50 values. We found that 20 µM ATRA treatment followed by dacarbazine was found to be more effective than dacarbazine alone. There was an indication that the combination of ATRA with dacarbazine (ATRA/dacarbazine) caused more apoptosis and necrosis in the melanoma cells (P<0.05). Furthermore, ATRA/dacarbazine treatment inhibited the cell at the G0/G1 phase, while dacarbazine alone inhibited the cells at S phase. CONCLUSION Collectively, combined treatment with ATRA and dacarbazine induced more apoptosis and enhanced the cell cycle arrest of CD117+ melanoma cells. These results suggested that ATRA increased the sensitivity of melanoma cells to the effect of dacarbazine.
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Affiliation(s)
- Bahareh Mohammadi Jobani
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elham Mohebi
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Nowruz Najafzadeh
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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Zhao X, Liu HQ, Wang LN, Yang L, Liu XL. Current and emerging molecular and epigenetic disease entities in acute myeloid leukemia and a critical assessment of their therapeutic modalities. Semin Cancer Biol 2020; 83:121-135. [PMID: 33242577 DOI: 10.1016/j.semcancer.2020.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 01/08/2023]
Abstract
Acute myeloid leukemia (AML) is the most frequently diagnosed acute leukemia, and its incidence increases with age. Although the etiology of AML remains unknown, exposure to genotoxic agents or some prior hematologic disorders could lead to the development of this condition. The pathogenesis of AML involves the development of malignant transformation of hematopoietic stem cells that undergo successive genomic alterations, ultimately giving rise to a full-blown disease. From the disease biology perspective, AML is considered to be extremely complex with significant genetic, epigenetic, and phenotypic variations. Molecular and cytogenetic alterations in AML include mutations in those subsets of genes that are involved in normal cell proliferation, maturation and survival, thus posing significant challenge to targeting these pathways without attendant toxicity. In addition, multiple malignant cells co-exist in the majority of AML patients. Individual subclones are characterized by unique genetic and epigenetic abnormalities, which contribute to the differences in their response to treatment. As a result, despite a dramatic progress in our understanding of the pathobiology of AML, not much has changed in therapeutic approaches to treat AML in the past four decades. Dose and regimen modifications with improved supportive care have contributed to improved outcomes by reducing toxicity-related side effects. Several drug candidates are currently being developed, including targeted small-molecule inhibitors, cytotoxic chemotherapies, monoclonal antibodies and epigenetic drugs. This review summarizes the current state of affairs in the pathobiological and therapeutic aspects of AML.
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Affiliation(s)
- Xin Zhao
- Department of Paediatrics, The First Hospital of Jilin University, Changchun, China
| | - Huan-Qiu Liu
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
| | - Li-Na Wang
- Department of Paediatrics, The First Hospital of Jilin University, Changchun, China
| | - Le Yang
- Department of Endocrinology, The People's Hospital of Jilin Province, Changchun, China.
| | - Xiao-Liang Liu
- Department of Hematology, The First Hospital of Jilin University, Changchun, China.
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Chen PH, Chung CM, Wang YY, Huang HW, Huang B, Lee KW, Yuan SS, Wu CW, Lin LS, Chan LP. CYP26A1 Is a Novel Biomarker for Betel Quid-Related Oral and Pharyngeal Cancers. Diagnostics (Basel) 2020; 10:diagnostics10110982. [PMID: 33233443 PMCID: PMC7700252 DOI: 10.3390/diagnostics10110982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/06/2020] [Accepted: 11/12/2020] [Indexed: 12/17/2022] Open
Abstract
Betel quid (BQ) has been classified as a Group I human carcinogen in light of evidence demonstrating an association with an elevated risk of oral and pharyngeal cancers. To date, the incidence rate of oral and pharynx cancers among Taiwanese men ranks the highest worldwide. However, no study has yet confirmed variants of CYP26A1 was associated with the risks of oral and pharyngeal cancers. A case-control study was conducted (n = 339). CYP26A1 polymorphism was performed using SNP assay. Real-time qRT-PCR and Western blotting were used to determine the levels of CYP26A1 expression. The cancer cell model involved treatment with arecoline. Our findings showed that the downregulation of CYP26A1 mRNA and protein expression are more frequently observed in cancerous tissues than adjacent normal tissues in patients with oral and pharynx cancers (p < 0.01). We found that CYP26A1 was downregulated as the arecoline dose increased. We hypothesized that lower levels of CYP26A1 mRNA expression can be utilized a clinically biomarker causes oral and pharynx cancers. Arecoline appears to modulate CYP26A1 expression through specific pathways. Carriers of CYP26A1 SNP, rs2068888 (G/G)/rs4418728 (G/G) and who have lower levels of CYP26A1 expression are associated with an increased risk of oral and pharyngeal cancers.
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Affiliation(s)
- Ping-Ho Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.-H.C.); (Y.-Y.W.)
- Institute of Biomedical Sciences, National Sun Yat-sen University, No. 70 Lienhai Road, Kaohsiung 80424, Taiwan;
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cohort Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Chia-Min Chung
- Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung 406040, Taiwan;
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan
| | - Yen-Yun Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.-H.C.); (Y.-Y.W.)
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hurng-Wern Huang
- Institute of Biomedical Sciences, National Sun Yat-sen University, No. 70 Lienhai Road, Kaohsiung 80424, Taiwan;
| | - Bin Huang
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ka-Wo Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan;
| | - Shyng-Shiou Yuan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Che-Wei Wu
- Cohort Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Lee-Shuan Lin
- Laboratory of Veterinary Diagnostic Imaging, Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912301, Taiwan;
| | - Leong-Perng Chan
- Cohort Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan;
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-7-312-1101; Fax: +886-7-315-7024
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Giuli MV, Hanieh PN, Giuliani E, Rinaldi F, Marianecci C, Screpanti I, Checquolo S, Carafa M. Current Trends in ATRA Delivery for Cancer Therapy. Pharmaceutics 2020; 12:E707. [PMID: 32731612 PMCID: PMC7465813 DOI: 10.3390/pharmaceutics12080707] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/12/2022] Open
Abstract
All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer.
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Affiliation(s)
- Maria Valeria Giuli
- Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.V.G.); (E.G.); (I.S.)
| | - Patrizia Nadia Hanieh
- Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy; (P.N.H.); (F.R.); (C.M.); (M.C.)
| | - Eugenia Giuliani
- Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.V.G.); (E.G.); (I.S.)
| | - Federica Rinaldi
- Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy; (P.N.H.); (F.R.); (C.M.); (M.C.)
| | - Carlotta Marianecci
- Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy; (P.N.H.); (F.R.); (C.M.); (M.C.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy; (M.V.G.); (E.G.); (I.S.)
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 04100 Latina, Italy
| | - Maria Carafa
- Department of Drug Chemistry and Technology, Sapienza University of Rome, 00185 Rome, Italy; (P.N.H.); (F.R.); (C.M.); (M.C.)
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Rashid A, Duan X, Gao F, Yang M, Yen A. Roscovitine enhances All-trans retinoic acid (ATRA)-induced leukemia cell differentiation: Novel effects on signaling molecules for a putative Cdk2 inhibitor. Cell Signal 2020; 71:109555. [PMID: 32032659 DOI: 10.1016/j.cellsig.2020.109555] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 12/31/2022]
Abstract
All-trans retinoic acid (ATRA)-based differentiation therapy has been unsuccessful in treating t(15;17) negative acute myeloid leukemia (AML) patients, motivating interest in combination therapies using ATRA plus other agents. Using the t (15, 17) negative HL-60 human myeloblastic leukemia model, we find that the cyclin-dependent kinase (CDK) inhibitor, roscovitine, augments signaling by an ATRA-induced macromolecular signalsome that propels differentiation and enhances ATRA-induced differentiation. Roscovitine co-treatment enhanced ATRA-induced expression of pS259- pS289/296/301- pS621-c-Raf, pS217/221-Mek, Src Family Kinases (SFKs) Lyn and Fgr and SFK Y416 phosphorylation, adaptor proteins c-Cbl and SLP-76, Vav, and acetylated 14-3-3 in the signalsome. Roscovitine enhanced ATRA-induced c-Raf interaction with Lyn, Vav, and c-Cbl. Consistent with signalsome hyper-activation, roscovitine co-treatment enhanced ATRA-induced G1/0 arrest and expression of differentiation markers, CD11b, ROS and p47 Phox. Because roscovitine regulated Lyn expression, activation and partnering, a stably transfected Lyn knockdown was generated from wt-parental cells to investigate its function in ATRA-induced differentiation. Lyn-knockdown enhanced ATRA-induced up-regulation of key signalsome molecules, c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, Vav1, SLP-76, and Fgr, but with essentially total loss of pY416-SFK. Compared to ATRA-treated wt-parental cells, differentiation markers p47 phox, CD11b, G1/G0 arrest and ROS production were enhanced in ATRA-treated Lyn-knockdown stable transfectants, and addition of roscovitine further enhanced these ATRA-inducible markers. The Lyn-knockdown cells expressed slightly higher c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, and SLP-76 than wt-parental cells, and this was associated with enhanced ATRA-induced upregulation of Fgr and cell differentiation, consistent with heightened signaling, suggesting that enhanced Fgr may have compensated for loss of Lyn to enhance differentiation in the Lyn-knockdown cells.
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Affiliation(s)
- Asif Rashid
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China; Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Xin Duan
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Feng Gao
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Mengsu Yang
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China.
| | - Andrew Yen
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
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Nahon P, Ganne-Carrié N. Management of patients with pre-therapeutic advanced liver fibrosis following HCV eradication. JHEP Rep 2019; 1:480-489. [PMID: 32039400 PMCID: PMC7005771 DOI: 10.1016/j.jhepr.2019.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/30/2019] [Accepted: 11/06/2019] [Indexed: 12/19/2022] Open
Abstract
Patients with HCV-related bridging fibrosis or cirrhosis remain at risk of developing life-threatening complications even after achieving a sustained virological response. Although it is reduced, the risk of liver-related events in these patients justifies their inclusion in surveillance programmes dedicated to the early detection of hepatocellular carcinoma and the screening for portal hypertension. Biochemical parameters or non-invasive tests might indicate the potential progression of liver injury despite viral clearance. Specific attention must be focused on the management of comorbidities, while dedicated educational programmes must be encouraged to increase compliance and commitment to surveillance. Better knowledge of the long-term evolution of these patients, who now live longer, is essential to improve risk stratification and refine screening strategies in this growing population.
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Key Words
- AFP, alpha-fetoprotein
- ALT, alanine aminotransferase
- APRI, AST-to-platelet ratio index
- AST, aspartate aminotransferase
- DAAs, direct-acting antivirals
- EHC, extrahepatic cancer
- FIB-4, fibrosis-4
- HCC, hepatocellular carcinoma
- HCV
- HR, hazard ratio
- Hepatocellular carcinoma
- LSM, liver stiffness measurement
- Liver failure
- MACEs, major adverse cardiovascular events
- PHT, portal hypertension
- Portal hypertension
- SMR, standardised mortality ratio
- SVR
- SVR, sustained virological response
- surveillance
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France
- University Paris 13, Sorbonne Paris Cité, “équipe labellisée Ligue Contre le Cancer”, F-93000 Bobigny, France
- INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010, Paris, France
| | - Nathalie Ganne-Carrié
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France
- University Paris 13, Sorbonne Paris Cité, “équipe labellisée Ligue Contre le Cancer”, F-93000 Bobigny, France
- INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010, Paris, France
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Liao H, Zhao S, Wang H, Liu Y, Zhang Y, Sun G. Self-Assembly Of Retinoid Nanoparticles For Melanoma Therapy. Int J Nanomedicine 2019; 14:7963-7973. [PMID: 31632011 PMCID: PMC6778447 DOI: 10.2147/ijn.s196974] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 07/27/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Amphiphilic fusion drugs are covalent conjugates of a lipophilic drug and a hydrophilic drug or their active fragments. These carrier-free self-assembly nanomaterials are helpful to co-deliver two synergic drugs to the same site regardless of pharmacokinetic properties of individual drugs. Retinoic hydroxamic acid (RHA) is a "fusion drug" of all-trans retinoic acid (ATRA) and vorinostat, a histone deacetylase (HDAC) inhibitor showing synergic effect with ATRA on cancer therapy. Although RHA was synthesized in 2005, its nanoscale self-assembly property, anticancer activity, and possible related mechanism are still unclear. METHODS RHA nanoparticles were observed under transmission electron microscope (TEM). Both in vitro cell viability, colony formation assay, and in vivo xenograft mouse tumor model were employed here to study anticancer activity of RHA nanoparticles. The putative synergic anticancer mechanism of activating retinoic acid receptor (RAR) and inhibiting HDAC were investigated via receptor inhibitor rescue assay and in vitro enzyme activity assay, respectively. RESULTS RHA could form nanoparticle formation by self-assembly and abrogates growth of several solid tumor cell lines even after RHA nanoparticles' washout. However, opposite to our initial hypothesis, pre-treating the melanoma cells with RAR antagonists showed no impact on inhibitory effect of RHA nanoparticles, which suggested that the target of the molecule on melanoma cells is not RAR and retinoid X receptor (RXR). Importantly, RHA nanoparticles inhibited the growth of xenograft tumors without obvious impact on haematological indexes and hepatorenal function of these tumor-bearing mice. CONCLUSION Our findings demonstrate the promise of RHA nanoparticles in treating malignant melanoma tumors with high efficacy and low toxicity.
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Affiliation(s)
- Han Liao
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing100049, People’s Republic of China
| | - Shan Zhao
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing100049, People’s Republic of China
| | - Huihui Wang
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing100049, People’s Republic of China
| | - Yang Liu
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
| | - Ying Zhang
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
| | - Guangwei Sun
- Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian116023, People’s Republic of China
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The potential of retinoids for combination therapy of lung cancer: Updates and future directions. Pharmacol Res 2019; 147:104331. [PMID: 31254665 DOI: 10.1016/j.phrs.2019.104331] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/23/2019] [Accepted: 06/25/2019] [Indexed: 12/20/2022]
Abstract
Lung cancer is the most common cancer-related death worldwide. Natural compounds have shown high biological and pharmaceutical relevance as anticancer agents. Retinoids are natural derivatives of vitamin A having many regulatory functions in the human body, including vision, cellular proliferation and differentiation, and activation of tumour suppressor genes. Retinoic acid (RA) is a highly active retinoid isoform with promising anti-lung cancer activity. The abnormal expression of retinoid receptors is associated with loss of anticancer activities and acquired resistance to RA in lung cancer. The preclinical promise has not translated to the general clinical utility of retinoids for lung cancer patients, especially those with a history of smoking. Newer retinoid nano-formulations and the combinatorial use of retinoids has been associated with lower toxicity and more favorably efficacy in both the preclinical and clinical settings. Here, we highlight epidemiological and clinical therapeutic studies involving retinoids and lung cancer. We also discuss the biological actions of retinoids in lung cancer, which include effects on cancer stem cell differentiation, angiogenesis, metastasis, and proliferative. We suggest that the use of retinoids in combination with conventional and targeted anticancer agents will broaden the utility of these potent anticancer compounds in the lung cancer clinic.
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Dobrotkova V, Chlapek P, Jezova M, Adamkova K, Mazanek P, Sterba J, Veselska R. Prediction of neuroblastoma cell response to treatment with natural or synthetic retinoids using selected protein biomarkers. PLoS One 2019; 14:e0218269. [PMID: 31188873 PMCID: PMC6561640 DOI: 10.1371/journal.pone.0218269] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 05/29/2019] [Indexed: 01/20/2023] Open
Abstract
Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.
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Affiliation(s)
- Viera Dobrotkova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska, Czech Republic
| | - Petr Chlapek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska, Czech Republic
| | - Marta Jezova
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavska, Czech Republic
| | - Katerina Adamkova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska, Czech Republic
| | - Pavel Mazanek
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni, Czech Republic
| | - Jaroslav Sterba
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni, Czech Republic
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, Pekarska, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Cernopolni, Czech Republic
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Jones T, Zhang B, Major S, Webb A. All-trans retinoic acid eluting poly(diol citrate) wafers for treatment of glioblastoma. J Biomed Mater Res B Appl Biomater 2019; 108:619-628. [PMID: 31087625 DOI: 10.1002/jbm.b.34416] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/15/2019] [Accepted: 04/25/2019] [Indexed: 12/23/2022]
Abstract
Current treatments for glioblastoma have failed to significantly increase patient survival, are extremely cytotoxic, can cause severe side effects, and are ineffective. Given these limitations, drugs other than cytotoxic chemotherapeutic agents are being explored. Recent studies show that all-trans retinoic acid (ATRA) could be effective on cancer cells as they have been shown to suppress carcinogenesis in a variety of tumor types and can reverse premalignant lesions and inhibit the development of secondary tumors in the head and neck of cancer patients. However, the therapeutic effects of retinoids such as ATRA are undermined by its rapid in vivo metabolism by cytochrome P450 enzymes, difficulty in crossing the blood-brain barrier, and sensitivity to isomerization/degradation. To overcome these limitations, we have developed a porous poly(1,8-octanediol-co-citrate; POC) wafer that stabilizes all-trans retinoic acid, while slowly releasing ATRA over 3 months. Release of ATRA from POC wafers inhibited proliferation of U87MG (glioblastoma) cells and caused upregulation in genes associated with differentiation into normal phenotype and apoptosis. Therefore, ATRA eluting poly(diol citrate) wafers are a promising treatment option compared to traditional cytotoxic chemotherapeutic agents.
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Affiliation(s)
- Tarielle Jones
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Bisheng Zhang
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Stephano Major
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
| | - Antonio Webb
- Department of Materials Science and Engineering, University of Florida, Gainesville, Florida
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Enikeev AD, Komelkov AV, Zborovskaya IB, Galetsky SA, Skryabin GO, Tchevkina EM. Non-canonical activity of retinoic acid in relation to the activation of protein kinases in transformed cells of different origin. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2018-5-4-127-130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Background.The non-canonical activity of retinoic acid (RA) was discovered relatively recently and consists in the rapid activation of intracellular signaling pathways by the mechanisms not related to the transcriptional activity of the RA nuclear receptors. Separate data suggest that this activity can stimulate the processes of malignancy and contribute to the formation of tumor cell resistance to RA as a therapeutic agent. However, little is known about the mechanisms of this activity. It is also unclear how universal this effect is; does the RA-dependent activation of different signaling protein kinases occur in the same cells, and whether activation of these kinases is interrelated.Materials and methods: cultivation of non-small cell lung cancer cells and neuroblastoma cells under standard conditions and with incubation with all-trans retinoic acid (ATRA); immunoblotting.Results. Here we studied the effect of ATRA on the activation of Akt and Erk1/2 protein kinases depending on the incubation time. The analysis revealed RA-dependent activation of both kinases in all studied non-small cell lung cancer and neuroblastoma cell lines. Activation of Akt and Erk1/2 occurred at five minutes of incubation, which corresponds to the non-transcriptional (non-canonical) activity of the RA, however, further activation kinetics of the two kinases differed essentially.Conclusion.We found that ATRA causes rapid activation of Erk1/2 and Akt protein kinases in both non-small cell lung cancer and neuroblastoma cells. The differences in the kinetics of RA-dependent stimulation of these two kinases suggest that their activation is mediated by independent mechanisms.
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Affiliation(s)
- A. D. Enikeev
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. V. Komelkov
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - I. B. Zborovskaya
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - S. A. Galetsky
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - G. O. Skryabin
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. M. Tchevkina
- Research Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
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Abstract
Retinoic acid receptor (RAR) signaling plays an important role in embryonic development and homeostasis of many tissues. At the cellular level, activation of RAR signaling often induces cell cycle arrest, differentiation, and apoptosis in many types of cells. Consequently, loss of normal RAR function in the presence of physiological levels of retinoic acid (RA) is often observed in cancers, and pharmacological reactivation of RAR signaling has been considered a promising strategy for cancer therapy and prevention. One of important mechanisms that regulate RAR activity in cancer cells is cross-talk with growth factor signaling, where activation of extracellular signal-regulated kinase (ERK) plays a major role in suppressing RAR transcriptional activity downstream of growth factor receptors. Conversely, strong activation of RAR can induce suppression of ERK activity by inducing expression of a phosphatase specific for ERK to exert tumor-suppressive activity in colorectal cancer. Here, we describe the basic methods to analyze interactions between RAR and ERK signaling in colorectal cancer cells.
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Jobani BM, Najafzadeh N, Mazani M, Arzanlou M, Vardin MM. Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44 + versus CD117 + melanoma cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 48:161-169. [PMID: 30195874 DOI: 10.1016/j.phymed.2018.05.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 04/14/2018] [Accepted: 05/18/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND All-trans retinoic acid (ATRA) is a differentiating agent that inhibits cancer cell growth during the cell cycle. However, despite its potent antitumor properties, some melanoma cells are resistant to ATRA therapy. PURPOSE Here, we hypothesized that allicin can sensitize malignant melanoma cells to ATRA treatment. To clarify this mechanism, we determined the sensitivity to ATRA, allicin and allicin/ATRA in CD44+ and CD117+ melanoma cell subpopulations. METHODS The CD44+and CD117+cells were sorted from A375 melanoma cell line using the magnetic-activated cell sorting (MACS). The potential anticancer effects of ATRA, allicin and allicin/ATRA were examined using cell proliferation MTT assay. In addition, flow cytometry was used to detect cell cycle arrest. The efficacy of the treatments in controlling cancer cell proliferation was assessed by quantitative realtime polymerase chain reaction (RT-PCR). RESULTS Here, we demonstrated that CD44+ melanoma cells were more resistant to allicin and ATRA than CD117+ cells. Importantly, we observed that allicin sensitized melanoma cell to ATRA-induced cell death. The combination treatment with allicin and ATRA significantly reduced the IC50 value obtained for ATRA alone in CD44+ melanoma cells. In CD44+ cells, the IC50 value of ATRA was 37.43 ± 0.54, while the IC50 value of allicin/ATRA treatment was 17.53 ± 0.2 µM. Allicin treatment resulted in significant increases in the percentage of cells at the G2/M and G0/G1 phases in the CD44+ and CD117+ cells, respectively. The combination treatment caused the inhibition of CD44+ and CD117+ melanoma cells at the S phases compared to ATRA alone. Allicin, ATRA, and allicin/ATRA increased the expression of cyclin D1 mRNA in both CD44+ and CD117+ cells. Allicin combination with ATRA increased the mRNA level of RARβ in CD117+ cells. Furthermore, allicin alone caused a remarkable reduction of MMP-9 mRNA expression in both CD44+ and CD117+ cells. In contrast, ATRA and the combination treatment significantly increased MMP-9 gene expression in CD44+ cells. CONCLUSION Overall, our results indicate that allicin reinforces the ATRA-mediated inhibitory effects on CD44+ and CD117+ melanoma cells and may provide a new approach for the treatment of malignant melanoma.
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Affiliation(s)
- Bahareh Mohammadi Jobani
- Research Laboratory for Embryology and Stem Cells, Department of Anatomy and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran; Department of Biochemistry, Ardabil University of Medical University, Ardabil, Iran; Student Research Committee, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Nowruz Najafzadeh
- Research Laboratory for Embryology and Stem Cells, Department of Anatomy and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mohammad Mazani
- Department of Biochemistry, Ardabil University of Medical University, Ardabil, Iran
| | - Mohsen Arzanlou
- Department of Microbiology, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mohammad Mohammadzadeh Vardin
- Research Laboratory for Embryology and Stem Cells, Department of Anatomy and Pathology, Ardabil University of Medical Sciences, Ardabil, Iran
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32
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MacDonald RJ, Bunaciu RP, Ip V, Dai D, Tran D, Varner JD, Yen A. Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells. Leuk Lymphoma 2018; 59:2941-2951. [PMID: 29569971 DOI: 10.1080/10428194.2018.1452213] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
The acute promyelocytic leukemia (APL) has been treated with all-trans retinoic acid (RA) for decades. While RA has largely been ineffective in non-APL AML subtypes, co-treatments combining RA and other agents are currently in clinical trials. Using the RA-responsive non-APL AML cell line HL-60, we tested the efficacy of the Src family kinase (SFK) inhibitor bosutinib on RA-induced differentiation. HL-60 has been recently shown to bear fidelity to a subtype of AML that respond to RA. We found that co-treatment with RA and bosutinib enhanced differentiation evidenced by increased CD11b expression, G1/G0 cell cycle arrest, and respiratory burst. Expression of the SFK members Fgr and Lyn was enhanced, while SFK activation was inhibited. Phosphorylation of several sites of c-Raf was increased and expression of AhR and p85 PI3K was enhanced. Expression of c-Cbl and mTOR was decreased. Our study suggests that SFK inhibition enhances RA-induced differentiation and may have therapeutic value in non-APL AML.
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Affiliation(s)
- Robert J MacDonald
- a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA
| | - Rodica P Bunaciu
- a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA
| | - Victoria Ip
- a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA
| | - David Dai
- b Robert Frederick Smith School of Chemical and Biomolecular Engineering , Cornell University , Ithaca , NY , USA
| | - David Tran
- a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA
| | - Jeffrey D Varner
- b Robert Frederick Smith School of Chemical and Biomolecular Engineering , Cornell University , Ithaca , NY , USA
| | - Andrew Yen
- a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA
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Narita S, Saito E, Sawada N, Shimazu T, Yamaji T, Iwasaki M, Ishihara J, Takachi R, Shibuya K, Inoue M, Tsugane S. Dietary consumption of antioxidant vitamins and subsequent lung cancer risk: The Japan Public Health Center-based prospective study. Int J Cancer 2018; 142:2441-2460. [PMID: 29355932 DOI: 10.1002/ijc.31268] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 12/13/2022]
Abstract
While many epidemiological studies have studied the association between lung cancer risk and fruits and vegetable consumption (the major sources of antioxidant vitamins), only a few have investigated the direct association with antioxidants in consideration of cancer subtypes and smoking status. Here, we examined the association between consumption of antioxidant vitamins and lung cancer risk in one of the largest prospective cohort studies in Japan. We investigated the association of dietary antioxidant vitamins intake, namely retinol, vitamin C, vitamin E, α-carotene, and β-carotene and subsequent incidence of lung cancer among 38,207 men and 41,498 women in the Japan Public Health Center-based prospective study. Cox proportional hazard regression was performed with adjustment for potential confounders and by strata of cancer subtypes and smoking status. Antioxidant and other dietary intakes were assessed using a food frequency questionnaire (FFQ). During 1,233,096 person-years of follow-up between 1995 and 2013, a total of 1,690 lung cancer cases were newly diagnosed. In a multivariate regression model, while higher retinol intake was positively associated with overall lung cancer risk in men (HR 1.26; 95% CI 1.05-1.51; ptrend = 0.003), the estimates were more evident with small cell carcinoma (HR 1.92; 95% CI 1.13-3.24; ptrend < 0.001). Null associations were observed for other antioxidant vitamins. Our prospective study suggests that higher consumption of retinol may be associated with an increased risk of lung cancer in men, especially with small cell carcinoma, although confirmation is required.
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Affiliation(s)
- Saki Narita
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Eiko Saito
- Division of Cancer Statistics and Integration, Center for Cancer Control and Information Services, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Norie Sawada
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Taichi Shimazu
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Taiki Yamaji
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Motoki Iwasaki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Junko Ishihara
- Department of Food and Life Science, School of Life and Environmental Science, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa, 252-5201, Japan
| | - Ribeka Takachi
- Department of Food Science and Nutrition, Faculty of Human Life and Environment, Nara Women's University, Kitauoya Higashimachi, Nara, 630-8506, Japan
| | - Kenji Shibuya
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Manami Inoue
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
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Chlapek P, Slavikova V, Mazanek P, Sterba J, Veselska R. Why Differentiation Therapy Sometimes Fails: Molecular Mechanisms of Resistance to Retinoids. Int J Mol Sci 2018; 19:ijms19010132. [PMID: 29301374 PMCID: PMC5796081 DOI: 10.3390/ijms19010132] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 12/28/2017] [Accepted: 12/29/2017] [Indexed: 12/12/2022] Open
Abstract
Retinoids represent a popular group of differentiation inducers that are successfully used in oncology for treatment of acute promyelocytic leukemia in adults and of neuroblastoma in children. The therapeutic potential of retinoids is based on their key role in the regulation of cell differentiation, growth, and apoptosis, which provides a basis for their use both in cancer therapy and chemoprevention. Nevertheless, patients treated with retinoids often exhibit or develop resistance to this therapy. Although resistance to retinoids is commonly categorized as either acquired or intrinsic, resistance as a single phenotypic feature is usually based on the same mechanisms that are closely related or combined in both of these types. In this review, we summarize the most common changes in retinoid metabolism and action that may affect the sensitivity of a tumor cell to treatment with retinoids. The availability of retinoids can be regulated by alterations in retinol metabolism or in retinoid intracellular transport, by degradation of retinoids or by their efflux from the cell. Retinoid effects on gene expression can be regulated via retinoid receptors or via other molecules in the transcriptional complex. Finally, the role of small-molecular-weight inhibitors of altered cell signaling pathways in overcoming the resistance to retinoids is also suggested.
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Affiliation(s)
- Petr Chlapek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
| | - Viera Slavikova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
| | - Pavel Mazanek
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
| | - Jaroslav Sterba
- International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
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35
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Dhiman VK, Bolt MJ, White KP. Nuclear receptors in cancer — uncovering new and evolving roles through genomic analysis. Nat Rev Genet 2017; 19:160-174. [DOI: 10.1038/nrg.2017.102] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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36
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An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program. Sci Rep 2017; 7:14327. [PMID: 29085021 PMCID: PMC5662654 DOI: 10.1038/s41598-017-14523-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/11/2017] [Indexed: 12/17/2022] Open
Abstract
In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPARg were critical to the ATRAinduced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.
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37
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Youn H, Lee HK, Sohn HR, Park UH, Kim EJ, Youn B, Um SJ. RaRF confers RA resistance by sequestering RAR to the nucleolus and regulating MCL1 in leukemia cells. Oncogene 2017; 37:352-362. [PMID: 28945224 DOI: 10.1038/onc.2017.329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 07/10/2017] [Accepted: 08/06/2017] [Indexed: 01/10/2023]
Abstract
Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA. RaRF was highly expressed in RA-resistant leukemia cells and its expression was strongly correlated with RA sensitivity. MCL1 was upregulated by RA treatment upon RaRF depletion, accompanying leukemic myeloblast differentiation, which is negatively regulated by ectopic RaRF expression. Collectively, we propose that RaRF may be a factor in the resistance mechanism and thus a potential target for leukemia therapy using RA.
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Affiliation(s)
- H Youn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea
| | - H-K Lee
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea
| | - H-R Sohn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea
| | - U-H Park
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea
| | - E-J Kim
- Department of Molecular Biology, Dankook University, Cheonan-si, Chungnam, Korea
| | - B Youn
- Department of Biological Sciences, Pusan National University, Gumjeong-gu, Busan 46241, Republic of Korea
| | - S-J Um
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea
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38
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Xu L, Zeng Z, Zhang W, Ren G, Ling X, Huang F, Xie P, Su Y, Zhang XK, Zhou H. RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner. Oncotarget 2017; 8:12311-12322. [PMID: 28129653 PMCID: PMC5355346 DOI: 10.18632/oncotarget.14812] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 12/27/2016] [Indexed: 01/25/2023] Open
Abstract
The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.
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Affiliation(s)
- Lin Xu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Zhiping Zeng
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Weidong Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Gaoang Ren
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Xiaobin Ling
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Fengyu Huang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Peizhen Xie
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
| | - Ying Su
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.,Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Xiao-Kun Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.,Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Hu Zhou
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China
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The role of prostate tumor overexpressed 1 in cancer progression. Oncotarget 2017; 8:12451-12471. [PMID: 28029646 PMCID: PMC5355357 DOI: 10.18632/oncotarget.14104] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 11/14/2016] [Indexed: 12/15/2022] Open
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40
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Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells. Mol Cell Biol 2017; 37:MCB.00012-17. [PMID: 28483913 DOI: 10.1128/mcb.00012-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 05/02/2017] [Indexed: 01/08/2023] Open
Abstract
Deregulated activation of RAS/extracellular signal-regulated kinase (ERK) signaling and defects in retinoic acid receptor (RAR) signaling are both implicated in many types of cancers. However, interrelationships between these alterations in regulating cancer cell fates have not been fully elucidated. Here, we show that RAS/ERK and RAR signaling pathways antagonistically interact with each other to regulate colorectal cancer (CRC) cell fates. We show that RAR signaling activation promotes spontaneous differentiation of CRC cells, while ERK activation suppresses it. Our microarray analyses identify genes whose expression levels are upregulated by RAR signaling. Notably, one of these genes, MKP4, encoding a member of dual-specificity phosphatases for mitogen-activated protein (MAP) kinases, mediates ERK inactivation upon RAR activation, thereby promoting the differentiation of CRC cells. Moreover, our results also show that RA induction of RAR target genes is suppressed by the ERK pathway activation. This suppression results from the inhibition of RAR transcriptional activity, which is shown to be mediated through an RIP140/histone deacetylase (HDAC)-mediated mechanism. These results identify antagonistic interactions between RAS/ERK and RAR signaling in the cell fate decision of CRC cells and define their underlying molecular mechanisms.
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41
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Desai KGH. Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer. J Biomed Mater Res B Appl Biomater 2017. [PMID: 28650116 DOI: 10.1002/jbm.b.33943] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Oral cancer is among the most prevalent cancers in the world. Moreover, it is one of the major health problems and causes of death in many regions of the world. The traditional treatment modalities include surgical removal, radiation therapy, systemic chemotherapy, or a combination of these methods. In recent decades, there has been significant interest in intraoral site-specific chemoprevention via local drug delivery using polymeric systems. Because of its easy accessibility and clear visibility, the oral mucosa is amenable for local drug delivery. A variety of polymeric systems-such as gels, tablets, films, patches, injectable systems (e.g., millicylindrical implants, microparticles, and in situ-forming depots), and nanosized carriers (e.g., polymeric nanoparticles, nanofibers, polymer-drug conjugates, polymeric micelles, nanoliposomes, nanoemulsions, and polymersomes)-have been developed and evaluated for the local delivery of natural and synthetic chemopreventive agents. The findings of in vitro, ex vivo, and in vivo studies and the positive outcome of clinical trials demonstrate that intraoral site-specific drug delivery is an attractive, highly effective and patient-friendly strategy for the management of oral cancer. Intraoral site-specific drug delivery provides unique therapeutic advantages when compared to systemic chemotherapy. Moreover, intraoral drug delivery systems are self-administrable and can be removed when needed, increasing patient compliance. This article covers important aspects and advances related to the design, development, and efficacy of polymeric systems for intraoral site-specific drug delivery. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1383-1413, 2018.
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Affiliation(s)
- Kashappa Goud H Desai
- Biopharmaceutical Product Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania, 19406
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Yao PL, Chen L, Dobrzański TP, Zhu B, Kang BH, Müller R, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor-β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation. Mol Carcinog 2017; 56:1472-1483. [PMID: 27996177 DOI: 10.1002/mc.22607] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 11/22/2016] [Accepted: 12/15/2016] [Indexed: 12/12/2022]
Abstract
Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator-activated receptor-β/δ, (PPARβ/δ) is known to promote terminal differentiation of many cell types. In the present study, PPARβ/δ was over-expressed in three human neuroblastoma cell lines, NGP, SK-N-BE(2), and IMR-32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid-induced differentiation to determine if PPARβ/δ and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All-trans-RA (atRA) decreased expression of SRY (sex determining region Y)-box 2 (SOX2), a stem cell regulator and marker of de-differentiation, in NGP and SK-N-BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR-32 cells carrying wild-type p53. Over-expression and/or ligand activation of PPARβ/δ reduced the average volume and weight of ectopic tumor xenografts from NGP, SK-N-BE(2), or IMR-32 cells compared to controls. Compared with that found with atRA, PPARβ/δ suppressed SOX2 expression in NGP and SK-N-BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR-32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over-expressing PPARβ/δ induces cell differentiation through p53- and SOX2-dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARα and PPARβ/δ may be suitable as an alternative therapeutic approach for RA-resistant neuroblastoma patients.
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Affiliation(s)
- Pei-Li Yao
- Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania
| | - Liping Chen
- Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania
| | - Tomasz P Dobrzański
- Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania
| | - Bokai Zhu
- Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania
| | - Boo-Hyon Kang
- Non-clinical Research Institute, Chemon, Jeil-Ri, Yangji-Myeon, Cheoin-Gu, Yongin-Si, Gyeonggi-Do, Korea
| | - Rolf Müller
- Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University, Marburg, Germany
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland
| | - Jeffrey M Peters
- Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania
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Pro-differentiating effects of a synthetic flavagline on human teratocarcinomal cancer stem-like cells. Cell Biol Toxicol 2016; 33:295-306. [DOI: 10.1007/s10565-016-9375-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 12/04/2016] [Indexed: 01/28/2023]
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44
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Arellano-Ortiz AL, Salcedo-Vargas M, Vargas-Requena CL, López-Díaz JA, De la Mora-Covarrubias A, Silva-Espinoza JC, Jiménez-Vega F. DNA Methylation of Cellular Retinoic Acid-Binding Proteins in Cervical Cancer. GENETICS & EPIGENETICS 2016; 8:53-57. [PMID: 27867303 PMCID: PMC5106192 DOI: 10.4137/geg.s40847] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/09/2016] [Accepted: 10/15/2016] [Indexed: 11/05/2022]
Abstract
This study determined the methylation status of cellular retinoic acid-binding protein (CRABP) gene promoters and associated them with demographic characteristics, habits, and the presence of human papilloma virus (HPV) in patients with cervical cancer (CC), low and high squamous intraepithelial lesions, and no intraepithelial lesion. Women (n = 158) were selected from the Colposcopy Clinic of Sanitary Jurisdiction II in Ciudad Juarez, Chihuahua, Mexico. Demographic characteristics and habit information were collected. Cervical biopsy and endocervical scraping were used to determine methylation in promoter regions by methylation-specific polymerase chain reaction technique. We found hemi-methylation patterns in the promoter regions of CRABP1 and CRABP2; there was 28.5% hemi-methylation in CRABP1 and 7.0% in that of CRABP2. Methylation in CRABP1 was associated with age (≥35 years, P = 0.002), family history of cancer (P = 0.032), the presence of HPV-16 (P = 0.013), and no alcohol intake (P = 0.035). These epigenetic changes could be involved in the CC process, and CRABP1 has the potential to be a predictive molecular marker of retinoid therapy response.
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Affiliation(s)
- Ana L. Arellano-Ortiz
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
| | - Mauricio Salcedo-Vargas
- Unidad de Investigación Médica de Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional-Siglo XXI, IMSS, Ciudad de México, México
| | - Claudia L. Vargas-Requena
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
| | - José A. López-Díaz
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
| | - Antonio De la Mora-Covarrubias
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
| | - Juan C. Silva-Espinoza
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
| | - Florinda Jiménez-Vega
- Laboratorio de Biotecnología, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua, México
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Rocchi S, Caretti F, Gentili A, Curini R, Perret D, Pérez-Fernández V. Quantitative profiling of retinyl esters in milk from different ruminant species by using high performance liquid chromatography-diode array detection-tandem mass spectrometry. Food Chem 2016; 211:455-64. [DOI: 10.1016/j.foodchem.2016.05.066] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 02/17/2016] [Accepted: 05/11/2016] [Indexed: 10/21/2022]
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Panebianco C, Oben JA, Vinciguerra M, Pazienza V. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings. Clin Exp Med 2016; 17:269-280. [PMID: 27655446 DOI: 10.1007/s10238-016-0438-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 09/08/2016] [Indexed: 12/16/2022]
Abstract
Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.
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Affiliation(s)
- Concetta Panebianco
- Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, Viale dei Cappuccini, 1, San Giovanni Rotondo, FG, Italy
| | - Jude A Oben
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, UK
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, UK.,Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czech Republic.,Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, Viale dei Cappuccini, 1, San Giovanni Rotondo, FG, Italy.
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47
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Zuo L, Yang X, Lu M, Hu R, Zhu H, Zhang S, Zhou Q, Chen F, Gui S, Wang Y. All-Trans Retinoic Acid Inhibits Human Colorectal Cancer Cells RKO Migration via Downregulating Myosin Light Chain Kinase Expression through MAPK Signaling Pathway. Nutr Cancer 2016; 68:1225-33. [PMID: 27564600 DOI: 10.1080/01635581.2016.1216138] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
All-trans-retinoic acid (ATRA) inhibits the invasive and metastatic potentials of various cancer cells. However, the underlying mechanism is unclear. Here, we demonstrate that ATRA inhibited colorectal cancer cells RKO (human colon adenocarcinoma cell) migration by downregulating cell movement and increasing cell adhesion. ATRA inhibited the expression and activation of myosin light chain kinase (MLCK) in RKO cells, while the expression level of MLC phosphatase (MLCP) had no change in RKO cells treated with or without ATRA. The expression and activity of MLC was also inhibited in RKO cells exposed to ATRA. Intriguingly, ATRA increased the expression of occludin messenger RNA (mRNA) and protein and its localization on cell membrane. However, ATRA did not change the expression of zonula occludens 1 (ZO-1), but increased the accumulation of ZO-1 on RKO cells membrane. ML-7, an inhibitor of MLCK, significantly inhibited RKO cell migration. Furthermore, knockdown of endogenous MLCK expression inhibited RKO migration. Mechanistically, we showed that MAPK-specific inhibitor PD98059 enhanced the inhibitory effect of ATRA on RKO migration. In contrast, phorbol 12-myristate 13-acetate (PMA) attenuated the effects of ATRA in RKO cells. Moreover, knocking down endogenous extracellular signal-regulated kinase (ERK) expression inhibited MLCK expression in the RKO cells. In conclusion, ATRA inhibits RKO migration by reducing MLCK expression via extracellular signal-regulated kinase 1/Mitogen-activated protein kinase (ERK1/MAPK) signaling pathway.
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Affiliation(s)
- Li Zuo
- a Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Xiaoping Yang
- a Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Man Lu
- b Department of Reproductive Center , The People's Liberation Army 105 Hospital , Anhui , China
| | - Ruolei Hu
- c Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Huaqing Zhu
- c Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Sumei Zhang
- c Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Qing Zhou
- c Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
| | - Feihu Chen
- d College of Pharmacy, Anhui Medical University , China
| | - Shuyu Gui
- e Department of Respiratory Medicine , the First Affiliated Hospital, Anhui Medical University , Anhui , China
| | - Yuan Wang
- f Laboratory of Molecular Biology and Department of Biochemistry , Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University , Anhui , China
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Auci DL, Egilmez NK. Synergy of Transforming Growth Factor Beta 1 and All Trans Retinoic Acid in the Treatment of Inflammatory Bowel Disease: Role of Regulatory T cells. ACTA ACUST UNITED AC 2016; 3. [PMID: 28603774 DOI: 10.15226/2374-815x/3/4/00166] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
| | - Nejat K Egilmez
- University of Louisville, Department of Microbiology and Immunology, Louisville, KY
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Oyama K, Kanki K, Shimizu H, Kono Y, Azumi J, Toriguchi K, Hatano E, Shiota G. Impact of Preferentially Expressed Antigen of Melanoma on the Prognosis of Hepatocellular Carcinoma. Gastrointest Tumors 2016; 3:128-135. [PMID: 28611979 DOI: 10.1159/000448137] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 06/24/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Retinoids, vitamin A and its derivatives, have an antitumor effect on hepatocellular carcinoma (HCC). The function of retinoids is exerted by the complex of retinoic acid (RA) with the heterodimer of retinoid X receptor and the RA receptor. The preferentially expressed antigen of melanoma (PRAME) acts as a dominant repressor of RA signaling by binding to the complex. The significance of PRAME on the prognosis of HCC remains to be clarified. METHODS PRAME mRNA expression was examined by quantitative real-time polymerase chain reaction in both tumor and non-tumor tissues of 100 HCC patients who received surgical resection. The effect of PRAME knockdown on DR5-mediated RA transcriptional activity was examined. RESULTS In tumor tissues, there were significant associations among PRAME expression, clinical stage, tumor markers, and tumor numbers. In non-tumor tissues, there were significant associations among PRAME expression, overall survival, and disease-free survival. The knockdown of PRAME caused no reduction in DR5-mediated transcriptional activity of RA, suggesting that PRAME acts via other mechanisms than the DR5 RA-responsive elements. CONCLUSION Our findings indicate that PRAME expression is a novel prognostic marker in HCC patients.
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Affiliation(s)
- Kenji Oyama
- Tottori University Hospital Cancer Center, Tottori University, Yonago, Japan.,Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Keita Kanki
- Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.,Department of Biomedical Engineering, Faculty of Engineering, Okayama University of Science, Okayama, Japan
| | - Hiroki Shimizu
- Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Yohei Kono
- Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Junya Azumi
- Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Kan Toriguchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
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50
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Marchwicka A, Cunningham A, Marcinkowska E, Brown G. Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review. Expert Opin Ther Pat 2016; 26:957-71. [PMID: 27336223 DOI: 10.1080/13543776.2016.1205586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Differentiation therapy using all-trans retinoic acid (ATRA) revolutionised the treatment of acute promyelocytic leukaemia to such an extent that it is now one of the most curable types of leukaemia, with ATRA and anthracycline-based chemotherapy providing cure rates above 80%. Isotretinoin is used to treat chronic acne. Here, we examine the information described in recent patents and the extent to which new findings are influencing extending retinoid-based differentiation therapy to other cancers, as well as the development of new therapies for other disorders. AREAS COVERED A search has been performed on the literature and worldwide patents filed during 2014 to the present time, focusing on synthetic agonists and antagonists of retinoic acid receptors and novel compositions for the delivery of these agents. EXPERT OPINION New potential therapeutic applications have been described, including lung, breast and head and neck cancers, T cell lymphoma and neurodegenerative, metabolic, ophthalmic, muscle, and inflammatory disorders. Recent patents have described the means to maximise retinoid activity. Two decades of efforts to extend retinoid-based therapies have been disappointing and new synthetic retinoids, target diseases and modes of delivery may well resolve this long standing issue.
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Affiliation(s)
- Aleksandra Marchwicka
- a Laboratory of Protein Biochemistry, Faculty of Biotechnology , University of Wroclaw , Wroclaw , Poland
| | - Alan Cunningham
- b Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences , University of Birmingham , Birmingham , UK
| | - Ewa Marcinkowska
- a Laboratory of Protein Biochemistry, Faculty of Biotechnology , University of Wroclaw , Wroclaw , Poland
| | - Geoffrey Brown
- c Institute of Clinical Sciences, College of Medical and Dental Sciences , University of Birmingham , Birmingham , UK
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