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Hunt S, Thyagarajan A, Sahu RP. Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer. Med Sci (Basel) 2025; 13:47. [PMID: 40407542 PMCID: PMC12101198 DOI: 10.3390/medsci13020047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 04/09/2025] [Accepted: 04/21/2025] [Indexed: 05/26/2025] Open
Abstract
Cancer is the second leading cause of mortality worldwide. Despite the available treatment options, a majority of cancer patients develop drug resistance, indicating the need for alternative approaches. Repurposed drugs, such as antiglycolytic and anti-microbial agents, have gained substantial attention as potential alternative strategies against different disease pathophysiologies, including lung cancer. To that end, multiple studies have suggested that the antiglycolytic dichloroacetate (DCA) and the antibiotic salinomycin (SAL) possess promising anticarcinogenic activity, attributed to their abilities to target the key metabolic enzymes, ion transport, and oncogenic signaling pathways involved in regulating cancer cell behavior, including cell survival and proliferation. We used the following searches and selection criteria. (1) Biosis and PubMed were used with the search terms dichloroacetate; salinomycin; dichloroacetate as an anticancer agent; salinomycin as an anticancer agent; dichloroacetate side effects; salinomycin side effects; salinomycin combination therapy; dichloroacetate combination therapy; and dichloroacetate or salinomycin in combination with other agents, including chemotherapy and tyrosine kinase inhibitors. (2) The exclusion criteria included not being related to the mechanisms of DCA and SAL or not focusing on their anticancer properties. (3) All the literature was sourced from peer-reviewed journals within a timeframe of 1989 to 2024. Importantly, experimental studies have demonstrated that both DCA and SAL exert promising anticarcinogenic properties, as well as having synergistic effects in combination with other therapeutic agents, against multiple cancer models. The goal of this review is to highlight the mechanistic workings and efficacy of DCA and SAL as monotherapies, and their combination with other therapeutic agents in various cancer models, with a major emphasis on non-small-cell lung cancer (NSCLC) treatment.
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Affiliation(s)
- Sunny Hunt
- Department of Chemistry and Biochemistry, Oberlin College, 173 W Lorain St, Oberlin, OH 44074, USA;
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Dayton, OH 45435, USA;
| | - Ravi P. Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Dayton, OH 45435, USA;
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2
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Singh U, Kokkanti RR, Patnaik S. Beyond chemotherapy: Exploring 5-FU resistance and stemness in colorectal cancer. Eur J Pharmacol 2025; 991:177294. [PMID: 39863147 DOI: 10.1016/j.ejphar.2025.177294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/28/2024] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.
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Affiliation(s)
- Ursheeta Singh
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, 751024, Odisha, India
| | - Rekha Rani Kokkanti
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, 751024, Odisha, India
| | - Srinivas Patnaik
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Bhubaneswar, 751024, Odisha, India.
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3
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Lu M, Liu Y, Zhu J, Shang J, Bai L, Jin Z, Li W, Hu Y, Zheng X, Qian J. Mapping the intellectual structure and emerging trends on nanomaterials in colorectal cancer: a bibliometric analysis from 2003 to 2024. Front Oncol 2025; 14:1514581. [PMID: 39845318 PMCID: PMC11750690 DOI: 10.3389/fonc.2024.1514581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Background Colorectal cancer (CRC) is one of thes most prevalent malignant tumors worldwide. Current therapeutic strategies for CRC have limitations, while nanomaterials show significant potential for diagnosing and treating CRC. This study utilizes bibliometric analysis to evaluate the current status and trends in this field. Methods Research on nanomaterials in CRC from 2003 to 2024 was retrieved from the Web of Science Core Collection (WOSCC). Tools such as CiteSpace, VOSviewer, RStudio, GraphPad Prism, and Excel were used to analyze trends and hotspots, covering publication trends, countries, institutions, authors, journals, co-citation analysis, and keywords. Visual maps were created to forecast future developments. Results The analysis includes 3,683 publications by 17,261 authors from 3,721 institutions across 100 countries/regions, published in 840 journals. Global publications have steadily increased, particularly since 2018. China leads in publication volume and citations, with six of the top ten research institutions and seven of the ten most cited authors, while the United States excels in citation impact and academic centrality. Both countries currently dominate the field, underscoring the urgent need for enhanced international collaboration. Ramezani M and Abnous K lead in publication volume and H-index, while Siegel RL is highly cited. The International Journal of Nanomedicine has the highest publication volume, while the Journal of Controlled Release is the most cited. In addition to "colorectal cancer" and "nanoparticles," the most common keyword is "drug delivery." Emerging research areas such as "metal-organic frameworks (MOFs)" and "green synthesis" are gaining attention as leading hotspots. Conclusion This study offers an in-depth analysis of the application of nanomaterials in CRC, promoting interdisciplinary collaboration and advancing scientific progress in this field.
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Affiliation(s)
- Man Lu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yi Liu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jin Zhu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiarong Shang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Lu Bai
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhichao Jin
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenting Li
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yue Hu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia Zheng
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jun Qian
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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4
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Maryiam A, Batool S, Ali Z, Zahid F, Alamri AH, Alqahtani T, Fatease AA, Lahiq AA, Khan MW, Din FU. Thermoresponsive biomaterial system of irinotecan and curcumin for the treatment of colorectal cancer: in-vitro and in-vivo investigations. Pharm Dev Technol 2025; 30:37-56. [PMID: 39726352 DOI: 10.1080/10837450.2024.2448334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/05/2024] [Accepted: 12/26/2024] [Indexed: 12/28/2024]
Abstract
This study aims to develop a thermoresponsive biomaterial system of irinotecan (IRT) and curcumin (CUR) nano-transferosomal gel (IRT-CUR-NTG) for targeting colorectal cancer (CRC). The IRT-CUR-NTs were statistically optimized and loaded into poloxamer-based thermosensitive gel. Transmission electron microscopy (TEM), Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) of the IRT-CUR-NTs were performed, whereas pH, gelation time, gelation temperature, gel and mucoadhesive strength of the IRT-CUR-NTG were investigated. In-vitro release and anticancer analyses were explored using HT29 cells. Additionally, in-vivo pharmacokinetics study was investigated followed by histopathological examination and in-vivo anticancer analysis. The PS, PDI, ZP, %EE of IRT and %EE of CUR were found to be 136.15 nm, 0.143, -15.5 mV, 95.05% and 85.12%, respectively. IRT-CUR-NTs exhibited spherical shape with no chemical interactions among the constituents. Similarly, IRT-CUR-NTG was homogenous gel suitable for rectal administration. IRT-CUR-NTG manifested prolonged release profiles of IRT and CUR. Moreover, a significantly enhanced (4-fold) bioavailability and no toxicity of IRT-CUR-NTG was observed when compared with conventional gel. IRT-CUR-NTs were found to be more effective against HT29 cell lines. In-vivo antitumor analysis demonstrated significantly reduced tumor volume and tumor mass after treatment with IRT-CUT-NTG, indicating improved antitumor effect. It can be concluded that IRT-CUR-NTG is suitable biomaterial system for colorectal cancer.
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Affiliation(s)
- Aleena Maryiam
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sibgha Batool
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Zakir Ali
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Fatima Zahid
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ali H Alamri
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Taha Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Adel Al Fatease
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Ahmed A Lahiq
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran, Saudi Arabi
| | - Muhammad Waseem Khan
- Institute of Pharmaceutical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Fakhar Ud Din
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
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5
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Azarian M, Ramezani Farani M, C Cho W, Asgharzadeh F, Yang YJ, Moradi Binabaj M, M Tambuwala M, Farahani N, Hushmandi K, Huh YS. Advancements in colorectal cancer treatment: The role of metal-based and inorganic nanoparticles in modern therapeutic approaches. Pathol Res Pract 2024; 264:155706. [PMID: 39527908 DOI: 10.1016/j.prp.2024.155706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 10/17/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Recent advances in the treatment of colorectal cancer (CRC) have highlighted the integration of metal-based nanoparticles into sophisticated therapeutic strategies. This examination delves into the potential applications of these nanoparticles, particularly in augmenting the effectiveness of photodynamic therapy (PDT) and targeted drug delivery systems. Metal nanoparticles, such as gold (Au), silver (Ag), and copper (Cu), possess distinctive characteristics that make them valuable in cancer treatment. Beyond their role as drug carriers, these nanoparticles actively engage in therapeutic processes like apoptosis induction, enhancement of photothermal effects, and generation of reactive oxygen species (ROS) crucial for tumor cell eradication. The utilization of metal nanoparticles in CRC therapy addresses significant challenges encountered with conventional treatments, such as drug resistance and systemic toxicity. For example, engineered Au nanoparticles enable targeted drug delivery, reducing off-target effects and maximizing therapeutic efficacy against cancerous cells. Their capacity to absorb near-infrared light allows for localized hyperthermia, effectively eliminating cancerous tissues. Similarly, Cu nanoparticles exhibit potential in overcoming drug resistance by enhancing the efficacy of traditional chemotherapeutic agents through ROS production and improved drug stability. This review underscores the significance of precision medicine in CRC care. Through the integration of metal nanoparticles alongside complementary biomarkers and personalized treatment strategies, a more efficient and tailored therapeutic approach can be achieved. The synergistic effect of PDT in combination with metal nanoparticles introduces a novel methodology to CRC treatment, offering a dual-action mechanism that enhances tumor targeting while minimizing undesirable effects. In conclusion, the integration of metal-based nanoparticles in CRC therapy marks a significant progress in oncological treatments. Continued research is imperative to comprehensively grasp their mechanisms, optimize their clinical utility, and address potential safety considerations. This thorough assessment aims to pave the way for future advancements in CRC treatment through the application of nanotechnology and personalized medicine strategies.
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Affiliation(s)
- Maryam Azarian
- Department of Bioanalytical Ecotoxicology,UFZ- Helmholtz Centre for Environmental Research, Leipzig, Germany; Department of Radiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marzieh Ramezani Farani
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Fereshteh Asgharzadeh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yu-Jeong Yang
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
| | - Maryam Moradi Binabaj
- Department of Nutrition, Food Sciences and Clinical Biochemistry, School of Medicine, Social Determinants of Health Research Center, Gonabad University of Medical Science, Gonabad, Iran
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, United Kingdom
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Yun Suk Huh
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea.
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Jasim SA, Salahdin OD, Malathi H, Sharma N, Rab SO, Aminov Z, Pramanik A, Mohammed IH, Jawad MA, Gabel BC. Targeting Hepatic Cancer Stem Cells (CSCs) and Related Drug Resistance by Small Interfering RNA (siRNA). Cell Biochem Biophys 2024; 82:3031-3051. [PMID: 39060914 DOI: 10.1007/s12013-024-01423-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 07/28/2024]
Abstract
Tumor recurrence after curative therapy and hepatocellular carcinoma (HCC) cells' resistance to conventional therapies is the reasons for the worse clinical results of HCC patients. A tiny population of cancer cells with a strong potential for self-renewal, differentiation, and tumorigenesis has been identified as cancer stem cells (CSCs). The discovery of CSC surface markers and the separation of CSC subpopulations from HCC cells have been made possible by recent developments in the study of hepatic (liver) CSCs. Hepatic CSC surface markers include epithelial cell adhesion molecules (EpCAM), CD133, CD90, CD13, CD44, OV-6, ALDH, and K19. CSCs have a significant influence on the development of cancer, invasiveness, self-renewal, metastasis, and drug resistance in HCC, and thus provide a therapeutic chance to treat HCC and avoid its recurrence. Therefore, it is essential to develop treatment approaches that specifically and effectively target hepatic stem cells. Given this, one potential treatment approach is to use particular small interfering RNA (siRNA) to target CSC, disrupting their behavior and microenvironment as well as changing their epigenetic state. The characteristics of CSCs in HCC are outlined in this study, along with new treatment approaches based on siRNA that may be used to target hepatic CSCs and overcome HCC resistance to traditional therapies.
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Affiliation(s)
| | | | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University, Bangalore, Karnataka, India
| | - Neha Sharma
- Chandigarh Pharmacy College, Chandigarh group of Colleges, Jhanjeri, 140307, Mohali, Punjab, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Israa Hussein Mohammed
- College of nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Benien C Gabel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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7
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Sakuraba S, Koizumi A, Iwasawa T, Ito T, Kato K. Serum EphA2 as a Promising Biomarker for the Early Detection and Diagnosis of Colorectal Cancer. Biomolecules 2024; 14:1504. [PMID: 39766211 PMCID: PMC11673381 DOI: 10.3390/biom14121504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/19/2024] [Accepted: 11/24/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND EphA2, a receptor-type tyrosine kinase, is overexpressed in several cancers, including colorectal cancer (CRC), and can be detected as soluble EphA2 in serum. This study aimed to investigate the relationship between soluble EphA2 and CRC. METHODS Serum samples were collected from 65 patients with CRC and 19 healthy individuals. Time-series changes in soluble EphA2 levels were measured in CRC cell lines to verify the release of EphA2 into the culture medium. RESULTS Soluble EphA2 levels were significantly higher in patients than in healthy individuals (p < 0.0001). Specifically, even in early-stage cancer, there was a notable difference between healthy individuals and patients with Stage I CRC (p = 0.00298), highlighting the potential of EphA2 as a biomarker for early detection. Additionally, correlations were observed with tumor size (p = 0.0346), depth of invasion (p = 0.0311), and lymphatic invasion (p = 0.0431). A receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.90 with 93.8% sensitivity and 78.9% specificity at a cutoff value of 448 pg/mL. CONCLUSIONS These findings suggest that serum EphA2 could serve as a valuable biomarker for the early detection of CRC, offering a practical and minimally invasive alternative to conventional tumor markers.
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Affiliation(s)
- Shunsuke Sakuraba
- Department of Surgery, Juntendo University Medical School, Shizuoka Hospital, Shizuoka 410-2295, Japan; (S.S.); (T.I.)
- Shizuoka Medical Research Center for Disaster, Shizuoka 410-2295, Japan;
| | - Akihiro Koizumi
- Department of Surgery, Juntendo University Medical School, Shizuoka Hospital, Shizuoka 410-2295, Japan; (S.S.); (T.I.)
| | - Takumi Iwasawa
- Shizuoka Medical Research Center for Disaster, Shizuoka 410-2295, Japan;
- Institute of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan
| | - Tomoaki Ito
- Department of Surgery, Juntendo University Medical School, Shizuoka Hospital, Shizuoka 410-2295, Japan; (S.S.); (T.I.)
- Shizuoka Medical Research Center for Disaster, Shizuoka 410-2295, Japan;
| | - Kazunori Kato
- Institute of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan
- Department of Nutrition Sciences, Graduate School of Health and Sports Sciences, Toyo University, Tokyo 115-8650, Japan
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8
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Pallathadka H, Hsu CY, Obaid Saleh R, Renuka Jyothi S, Kumar A, Yumashev A, Sinha A, Hussein Zwamel A, Abed Jawad M, Alsaadi SB. Specific small interfering RNAs (siRNAs) for targeting the metastasis, immune responses, and drug resistance of colorectal cancer cells (CRC). Int Immunopharmacol 2024; 140:112730. [PMID: 39083927 DOI: 10.1016/j.intimp.2024.112730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/05/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
Colorectal cancer (CRC) involves various genetic alterations, with liver metastasis posing a significant clinical challenge. Furthermore, CRC cells mostly show an increase in resistance to traditional treatments like chemotherapy. It is essential to investigate more advanced and effective therapies to prevent medication resistance and metastases and extend patient life. As a result, it is anticipated that small interfering RNAs (siRNAs) would be exceptional instruments that can control gene expression by RNA interference (RNAi). In eukaryotes, RNAi is a biological mechanism that destroys specific messenger RNA (mRNA) molecules, thereby inhibiting gene expression. In the management of CRC, this method of treatment represents a potential therapeutic agent. However, it is important to acknowledge that siRNA therapies have significant issues, such as low serum stability and nonspecific absorption into biological systems. Delivery mechanisms are thus being created to address these issues. In the current work, we address the potential benefits of siRNA therapy and outline the difficulties in treating CRCby focusing on the primary signaling pathways linked to metastasis as well as genes implicated in the multi-drug resistance (MDR) process.
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Affiliation(s)
| | - Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona 85004, USA.
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq.
| | - S Renuka Jyothi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Ashwani Kumar
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Russia.
| | - Aashna Sinha
- School of Applied and Life Sciences, Divison of Research and Innovation Uttaranchal University, Dehradun, Uttarakhand, India
| | - Ahmed Hussein Zwamel
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique college, the Islamic University of Babylon, Babylon, Iraq.
| | | | - Salim B Alsaadi
- Department of Pharmaceutics, Al-Hadi University College, Baghdad 10011, Iraq.
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9
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Kumari B, Tiwari A, Meena S, Ahirwar DK. Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets. Cancers (Basel) 2024; 16:3134. [PMID: 39335106 PMCID: PMC11429849 DOI: 10.3390/cancers16183134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.
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Affiliation(s)
- Beauty Kumari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Aniket Tiwari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Sakshi Meena
- School of Life Sciences, Devi Ahilya Vishwavidyalaya Indore, Indore 452001, Madhya Pradesh, India;
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
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10
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Wu J, Li W, Su J, Zheng J, Liang Y, Lin J, Xu B, Liu Y. Integration of single-cell sequencing and bulk RNA-seq to identify and develop a prognostic signature related to colorectal cancer stem cells. Sci Rep 2024; 14:12270. [PMID: 38806611 PMCID: PMC11133358 DOI: 10.1038/s41598-024-62913-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024] Open
Abstract
The prognosis for patients with colorectal cancer (CRC) remains worse than expected due to metastasis, recurrence, and resistance to chemotherapy. Colorectal cancer stem cells (CRCSCs) play a vital role in tumor metastasis, recurrence, and chemotherapy resistance. However, there are currently no prognostic markers based on CRCSCs-related genes available for clinical use. In this study, single-cell transcriptome sequencing was employed to distinguish cancer stem cells (CSCs) in the CRC microenvironment and analyze their properties at the single-cell level. Subsequently, data from TCGA and GEO databases were utilized to develop a prognostic risk model for CRCSCs-related genes and validate its diagnostic performance. Additionally, functional enrichment, immune response, and chemotherapeutic drug sensitivity of the relevant genes in the risk model were investigated. Lastly, the key gene RPS17 in the risk model was identified as a potential prognostic marker and therapeutic target for further comprehensive studies. Our findings provide new insights into the prognostic treatment of CRC and offer novel perspectives for a systematic and comprehensive understanding of CRC development.
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Affiliation(s)
- Jiale Wu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Wanyu Li
- Well Lead Medical Co., Ltd., Guangzhou, 511434, Guangdong, China
| | - Junyu Su
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Jiamin Zheng
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Yanwen Liang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China
| | - Jiansuo Lin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, 523808, Guangdong, China
| | - Bilian Xu
- School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China.
| | - Yi Liu
- School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China.
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11
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Ortega Duran M, Shaheed SU, Sutton CW, Shnyder SD. A Proteomic Investigation to Discover Candidate Proteins Involved in Novel Mechanisms of 5-Fluorouracil Resistance in Colorectal Cancer. Cells 2024; 13:342. [PMID: 38391955 PMCID: PMC10886605 DOI: 10.3390/cells13040342] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/31/2024] [Accepted: 02/10/2024] [Indexed: 02/24/2024] Open
Abstract
One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.
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Affiliation(s)
- Mario Ortega Duran
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
| | - Sadr ul Shaheed
- Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9BQ, UK;
| | - Christopher W. Sutton
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
| | - Steven D. Shnyder
- Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK; (M.O.D.); (C.W.S.)
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12
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Sharma NK, Bahot A, Sekar G, Bansode M, Khunteta K, Sonar PV, Hebale A, Salokhe V, Sinha BK. Understanding Cancer's Defense against Topoisomerase-Active Drugs: A Comprehensive Review. Cancers (Basel) 2024; 16:680. [PMID: 38398072 PMCID: PMC10886629 DOI: 10.3390/cancers16040680] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
In recent years, the emergence of cancer drug resistance has been one of the crucial tumor hallmarks that are supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters, and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often result in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores the use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.
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Affiliation(s)
- Nilesh Kumar Sharma
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Anjali Bahot
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Gopinath Sekar
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Mahima Bansode
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Kratika Khunteta
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Priyanka Vijay Sonar
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Ameya Hebale
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Vaishnavi Salokhe
- Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; (N.K.S.); (A.B.); (G.S.); (M.B.); (K.K.); (P.V.S.); (A.H.); (V.S.)
| | - Birandra Kumar Sinha
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
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13
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Lawler T, Parlato L, Warren Andersen S. Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control 2024; 35:223-239. [PMID: 37688643 PMCID: PMC11090693 DOI: 10.1007/s10552-023-01783-y] [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: 03/21/2023] [Accepted: 08/21/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin-Madison, Suite 1007B, WARF, 610 Walnut Street, Madison, WI, 53726, USA.
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14
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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15
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Xiao Y, Guo G, Wang H, Peng B, Lin Y, Qu G, Li B, Jiang Z, Zhang F, Wu J, Liang M. Curcumin/L-OHP co-loaded HAP for cGAS-STING pathway activation to enhance the natural immune response in colorectal cancer. Bioeng Transl Med 2024; 9:e10610. [PMID: 38193125 PMCID: PMC10771561 DOI: 10.1002/btm2.10610] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/30/2023] [Accepted: 09/23/2023] [Indexed: 01/10/2024] Open
Abstract
Insufficient immune cell infiltration into the tumor microenvironment (TME) greatly compromises the clinical application of immune-checkpoint inhibitors (ICIs)-based immunotherapy. Recent findings have shown that activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can enhance natural immunity and increase lymphocyte infiltration into the TME, which presents a promising strategy for cancer immunotherapy. In this study, we constructed hydroxyapatite nanoparticles co-loaded with curcumin and L-oxaliplatin (Cur/L-OHP@HAP NPs). We analyzed the particle-size distribution, zeta potential, spectral characteristics (Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, ultraviolet-visible spectroscopy), and drug-release properties of the Cur/L-OHP@HAP NPs. The cellular uptake of the Cur/L-OHP@HAP NPs detected by flow cytometry and confocal laser-scanning microscopy. We comprehensively evaluated the anti-tumor properties and immune-activating effects of the NPs, both in vitro and in vivo. Physicochemical characterizations demonstrated that the Cur/L-OHP@HAP NPs were successfully synthesized and were capable of pH-dependent drug release. Notably, the Cur/L-OHP@HAP NPs efficiently entered cancer cells, after which the released L-OHP induced nuclear DNA (nDNA) damage to some extent. HAP promoted the release of intracellular Ca2+ stores in cancer cells, and curcumin inhibited Ca2+ efflux, resulting in intracellular Ca2+ overload and the release of mitochondrial DNA (mtDNA). Damage to both nDNA and mtDNA greatly stimulated the cGAS-STING pathway, thereby activating natural immunity, accompanied by immune cell recruitment to the TME. In summary, the Cur/L-OHP@HAP NPs show good prospects for improving cancer immunotherapy.
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Affiliation(s)
- Yao Xiao
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Guohu Guo
- Department of Vascular and Gastroenterology SurgerySecond Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Huaiming Wang
- Department of Colorectal Surgery, Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affilliated Hospital, Sun Yat‐sen UniversityGuangzhouGuangdongP.R. China
| | - Bin Peng
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Yinglin Lin
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Gaowen Qu
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Ben Li
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Zhaojun Jiang
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Fan Zhang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- Department of Gastrointestinal SurgeryThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
| | - Jiaming Wu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Jiaxing UniversityJiaxingChina
| | - Min Liang
- Department of OncologyThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityGuangzhouChina
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16
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Hameed H, Faheem S, Zaman M, Khan MA, Ghumman SA, Sarwar HS, Mahmood A. Multiomics approaches in cancer. BIOLOGICAL INSIGHTS OF MULTI-OMICS TECHNOLOGIES IN HUMAN DISEASES 2024:53-72. [DOI: 10.1016/b978-0-443-23971-7.00003-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Osei GY, Adu-Amankwaah J, Koomson S, Beletaa S, Ahmad MK, Asiamah EA, Smith-Togobo C, Abdul Razak SR. Revolutionizing colorectal cancer treatment: unleashing the potential of miRNAs in targeting cancer stem cells. Future Oncol 2023; 19:2369-2382. [PMID: 37970643 DOI: 10.2217/fon-2023-0426] [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] [Indexed: 11/17/2023] Open
Abstract
Colorectal cancer (CRC) is a significant contributor to cancer mortality worldwide, and the presence of cancer stem cells (CSC) represents a major challenge for achieving effective treatment. miRNAs have emerged as critical regulators of gene expression, and recent studies have highlighted their role in regulating stemness and therapeutic resistance in CRC stem cells. This review highlights the mechanisms of CSC development, therapy resistance and the potential of miRNAs as therapeutic targets for CRC. It emphasizes the promise of miRNAs as a novel approach to CRC treatment and calls for further research to explore effective miRNA-based therapies and strategies for delivering miRNAs to CSCs in vivo.
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Affiliation(s)
- George Yiadom Osei
- Department of Biomedical Sciences, Advanced Medical & Dental Institute, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia
- Department of Medical Laboratory Sciences, University of Health & Allied Sciences, PMB 31, Ho, Ghana
| | - Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Selina Koomson
- Department of Medical Laboratory Sciences, University of Health & Allied Sciences, PMB 31, Ho, Ghana
| | - Solomon Beletaa
- Department of Medical Laboratory Sciences, University of Health & Allied Sciences, PMB 31, Ho, Ghana
| | - Muhammad Khairi Ahmad
- Department of Biomedical Sciences, Advanced Medical & Dental Institute, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia
| | - Emmanuel Akomanin Asiamah
- Department of Medical Laboratory Sciences, University of Health & Allied Sciences, PMB 31, Ho, Ghana
- Discipline of Public Health Medicine, School of Nursing & Public Health, University of KwaZulu-Natal, Durban, 4001, South Africa
- Cancer & Infectious Diseases Epidemiology Research Unit (CIDERU), College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
| | - Cecilia Smith-Togobo
- Department of Medical Laboratory Sciences, University of Health & Allied Sciences, PMB 31, Ho, Ghana
| | - Siti Razila Abdul Razak
- Department of Biomedical Sciences, Advanced Medical & Dental Institute, Universiti Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Malaysia
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18
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Thandar M, Zhu Y, Zhang X, Chen Z, Zhao Y, Huang S, Chi P. Construction and validation of stemness-related lncRNA pair signature for predicting prognosis in colorectal cancer. J Cancer Res Clin Oncol 2023; 149:11815-11828. [PMID: 37410143 DOI: 10.1007/s00432-023-05047-9] [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: 05/14/2023] [Accepted: 06/28/2023] [Indexed: 07/07/2023]
Abstract
PURPOSE The purpose of this study was to identify a prognostic signature based on stemness-related differentially expressed lncRNAs in colorectal cancer (CRC) and to investigate their potential as biomarkers for diagnosis, prognosis, and therapeutic targets. METHODS Stemness-related genes were collected from the TCGA cohort, and 13 differently expressed stemness-related lncRNAs were identified as prognostic factors for CRC using Kaplan-Meier analysis. A risk model was constructed based on the calculated risk score as a novel independent prognostic factor for CRC patients. The study also investigated the association between the risk model and immune checkpoints and m6A differentiation gene expression. qRT-PCR analysis was performed to validate the expression of differentially expressed stemness-related lncRNAs in CRC cell lines compared to normal colon mucosal cell line. RESULTS The low-risk lncRNAs were associated with higher survival in CRC patients (Kaplan-Meier analysis, P < 0.001). The risk model was a significant independent prognostic factor for CRC patients. Type I INF response was statistically significant between low- and high-risk groups. CD44, CD70, PVR, TNFSF4, BTNL2, CD40, these immune checkpoints were expressed differently between two risk groups. There was a significant difference between m6A differentiation gene expression such as METTL3, METTL14, WTAP, RBM15, ZC3H13, YTHDC2, YTHDF2, ALKBH5. qRT-PCR analysis validated that there were five up-regulated and eight down-regulated differently expressed stemness-related lncRNAs in CRC cell lines compared to the normal colon mucosal cell line. CONCLUSION This study suggests that the 13 CRC stemness-related lncRNA signature could become a promising and reliable prognostic factor for colorectal cancer. The risk model based on the calculated risk score may have implications for personalized medicine and targeted therapies for CRC patients. The study also suggests that immune checkpoints and m6A differentiation genes may play important roles in the development and progression of CRC.
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Affiliation(s)
- Mya Thandar
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yuanchang Zhu
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xueying Zhang
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zhifen Chen
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Yuena Zhao
- The Fifth People's Hospital of Dalian, Dalian, Liaoning Province, China
| | - Shenghui Huang
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China.
| | - Pan Chi
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China.
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19
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Shi M, An G, Chen N, Jia J, Cui X, Zhan T, Ji D. UVRAG Promotes Tumor Progression through Regulating SP1 in Colorectal Cancer. Cancers (Basel) 2023; 15:2502. [PMID: 37173968 PMCID: PMC10177159 DOI: 10.3390/cancers15092502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer. The ultraviolet radiation resistance-associated gene (UVRAG) plays a role in autophagy and has been implicated in tumor progression and prognosis. However, the role of UVRAG expression in CRC has remained elusive. In this study, the prognosis was analyzed via immunohistochemistry, and the genetic changes were compared between the high UVRAG expression group and the low UVRAG expression group using RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) data, and genetic changes were then identified by in vitro experiments. It was found that UVRAG could enhance tumor migration, drug resistance, and CC motif chemokine ligand 2 (CCL2) expression to recruit macrophages by upregulating SP1 expression, resulting in poor prognosis of CRC patients. In addition, UVRAG could upregulate the expression of programmed death-ligand 1 (PD-L1). In summary, the relationship between UVRAG expression and the prognosis of CRC patients as well as the potential mechanisms in CRC were explored, providing evidence for the treatment of CRC.
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Affiliation(s)
- Mengyuan Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Guo An
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Nan Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jinying Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xinxin Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Tiancheng Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Dengbo Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China
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20
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Taib N, Merhi M, Inchakalody V, Mestiri S, Hydrose S, Makni-Maalej K, Raza A, Sahir F, Azizi F, Nizamuddin PB, Fernandes Q, Yoosuf ZSKM, Almoghrabi S, Al-Zaidan L, Shablak A, Uddin S, Maccalli C, Al Homsi MU, Dermime S. Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy. J Transl Med 2023; 21:235. [PMID: 37004094 PMCID: PMC10067322 DOI: 10.1186/s12967-023-04073-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
BACKGROUND The mechanism of tumor immune escape and progression in colorectal cancer (CRC) is widely investigated in-vitro to help understand and identify agents that might play a crucial role in response to treatment and improve the overall survival of CRC patients. Several mechanisms of immune escape and tumor progression, including expression of stemness markers, inactivation of immunoregulatory genes by methylation, and epigenetic silencing, have been reported in CRC, indicating the potential of demethylating agents as anti-cancer drugs. Of these, a chemotherapeutic demethylating agent, Decitabine (DAC), has been reported to induce a dual effect on both DNA demethylation and histone changes leading to an increased expression of target biomarkers, thus making it an attractive anti-tumorigenic drug. METHODS We compared the effect of DAC in primary 1076 Col and metastatic 1872 Col cell lines isolated and generated from patients' tumor tissues. Both cell lines were treated with DAC, and the expression of the NY-ESO-1 cancer-testis antigen, the PD-L1 immunoinhibitory marker, and the CD44, Nanog, KLF-4, CD133, MSI-1 stemness markers were analyzed using different molecular and immunological assays. RESULTS DAC treatment significantly upregulated stemness markers in both primary 1076 Col and meta-static 1872 Col cell lines, although a lower effect occurred on the latter: CD44 (7.85 fold; ***p = 0.0001 vs. (4.19 fold; *p = 0.0120), Nanog (4.1 fold; ***p < 0.0001 vs.1.69 fold; ***p = 0.0008), KLF-4 (4.33 fold; ***p < 0.0001 vs.2.48 fold; ***p = 0.0005), CD133 (16.77 fold; ***p = 0.0003 vs.6.36 fold; *p = 0.0166), and MSI-1 (2.33 fold; ***p = 0.0003 vs.2.3 fold; ***p = 0.0004), respectively. Interestingly, in the metastatic 1872 Col cells treated with DAC, the expression of both PD-L1 and NY-ESO-1 was increased tenfold (*p = 0.0128) and fivefold (***p < 0.0001), respectively. CONCLUSIONS We conclude that the upregulation of both stemness and immune checkpoint markers by DAC treatment on CRC cells might represent a mechanism of immune evasion. In addition, induction of NY-ESO-1 may represent an immuno-therapeutic option in metastatic CRC patients. Finally, the combination of DAC and anti-PD-1/anti-PD-L1 antibodies treatment should represent a potential therapeutic intervention for this group of patients.
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Affiliation(s)
- Nassiba Taib
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Varghese Inchakalody
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Sarra Mestiri
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Shereena Hydrose
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Karama Makni-Maalej
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Afsheen Raza
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Fairooz Sahir
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Fouad Azizi
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Parveen B Nizamuddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Queenie Fernandes
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- College of Medicine, Qatar University, 2713, Doha, Qatar
| | - Zeenath Safira K M Yoosuf
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, 34110, Doha, Qatar
| | - Salam Almoghrabi
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Lobna Al-Zaidan
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Alaaeldin Shablak
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, 2030, Doha, Qatar
- Laboratory Animal Research Center, Qatar University, 2713, Doha, Qatar
| | - Cristina Maccalli
- Laboratory of Immune and Biological Therapy, Human Immunology Department, Research Branch, Sidra Medicine, 26999, Doha, Qatar
| | | | - Said Dermime
- Translational Cancer Research Facility, National Center for Cancer Care and Research/Translational Research Institute, Hamad Medical Corporation, 2030, Doha, Qatar.
- National Center for Cancer Care and Research, Hamad Medical Corporation, 2030, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University, 34110, Doha, Qatar.
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21
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Shi ZD, Pang K, Wu ZX, Dong Y, Hao L, Qin JX, Wang W, Chen ZS, Han CH. Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduct Target Ther 2023; 8:113. [PMID: 36906600 PMCID: PMC10008648 DOI: 10.1038/s41392-023-01383-x] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/07/2022] [Accepted: 02/20/2023] [Indexed: 03/13/2023] Open
Abstract
Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.
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Affiliation(s)
- Zhen-Duo Shi
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China.,School of Life Sciences, Jiangsu Normal University, Jiangsu, China.,Department of Urology, Heilongjiang Provincial Hospital, Heilongjiang, China
| | - Kun Pang
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yang Dong
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Lin Hao
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Jia-Xin Qin
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Wei Wang
- Department of Medical College, Southeast University, Nanjing, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Cong-Hui Han
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China. .,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China. .,School of Life Sciences, Jiangsu Normal University, Jiangsu, China. .,Department of Urology, Heilongjiang Provincial Hospital, Heilongjiang, China.
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22
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Yang Y, Meng WJ, Wang ZQ. MicroRNAs (miRNAs): Novel potential therapeutic targets in colorectal cancer. Front Oncol 2022; 12:1054846. [PMID: 36591525 PMCID: PMC9794577 DOI: 10.3389/fonc.2022.1054846] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the most common malignant tumor and one of the most lethal malignant tumors in the world. Despite treatment with a combination of surgery, radiotherapy, and/or systemic treatment, including chemotherapy and targeted therapy, the prognosis of patients with advanced CRC remains poor. Therefore, there is an urgent need to explore novel therapeutic strategies and targets for the treatment of CRC. MicroRNAs (miRNAs/miRs) are a class of short noncoding RNAs (approximately 22 nucleotides) involved in posttranscriptional gene expression regulation. The dysregulation of its expression is recognized as a key regulator related to the development, progression and metastasis of CRC. In recent years, a number of miRNAs have been identified as regulators of drug resistance in CRC, and some have gained attention as potential targets to overcome the drug resistance of CRC. In this review, we introduce the miRNAs and the diverse mechanisms of miRNAs in CRC and summarize the potential targeted therapies of CRC based on the miRNAs.
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23
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Tan B, Zhang J, Wang W, Ma H, Yang Y. Tumor-suppressive E3 ubiquitin ligase CHIP inhibits the PBK/ERK axis to repress stem cell properties and radioresistance in non-small cell lung cancer. Apoptosis 2022; 28:397-413. [PMID: 36436119 DOI: 10.1007/s10495-022-01789-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2022] [Indexed: 11/28/2022]
Abstract
Recently, radioresistant cancer cells surviving radiotherapy have been suggested to show more aggressive phenotypes than parental cells, and the underlying mechanisms may be associated with cancer stem cells. This study provided novel mechanistic insights for E3 ubiquitin ligase CHIP in stem cell properties and radioresistance of non-small cell lung cancer (NSCLC). After bioinformatic prediction for key genes involved, NSCLC tissues and cells were collected to measure the expression of CHIP and PBK. E3 ubiquitin ligase CHIP was poorly expressed, while PBK was highly expressed in NSCLC tissues and cells. CHIP reduced the protein stability of PBK through the ubiquitin-protease pathway to repress the activation of ERK pathway. Based on the gain- or loss-of-function experiments, it was noted that restoration of CHIP curtailed stem cell properties and radioresistance in NSCLC, as manifested by inhibited sphere formation and cell proliferation, decreased number of CD133+CD44+ cells and expression of OCT4, SOX2, and NANOG, as well as facilitated apoptosis of NSCLC cells. Besides, in vivo animal experiments further confirmed that CHIP restrained tumorigenic ability and improved radiosensitivity of NSCLC cells by inhibiting PBK/ERK axis. Collectively, CHIP suppressed stem cell properties and radioresistance of NSCLC cells by inhibiting PBK/ERK axis, therefore offering a potential therapeutic target for enhancing efficacy of radiotherapy.
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Affiliation(s)
- Bo Tan
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui, Zhengzhou, 450008, Henan, China.
| | - Jingwei Zhang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui, Zhengzhou, 450008, Henan, China
| | - Wen Wang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui, Zhengzhou, 450008, Henan, China
| | - Haibo Ma
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yuanyuan Yang
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui, Zhengzhou, 450008, Henan, China
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24
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Fatfat Z, Fatfat M, Gali-Muhtasib H. Micelles as potential drug delivery systems for colorectal cancer treatment. World J Gastroenterol 2022; 28:2867-2880. [PMID: 35978871 PMCID: PMC9280727 DOI: 10.3748/wjg.v28.i25.2867] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/22/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.
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Affiliation(s)
- Zaynab Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Maamoun Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
- Center for Drug Discovery, American University of Beirut, Beirut 1107 2020, Lebanon
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25
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Paskeh MDA, Saebfar H, Mahabady MK, Orouei S, Hushmandi K, Entezari M, Hashemi M, Aref AR, Hamblin MR, Ang HL, Kumar AP, Zarrabi A, Samarghandian S. Overcoming doxorubicin resistance in cancer: siRNA-loaded nanoarchitectures for cancer gene therapy. Life Sci 2022; 298:120463. [DOI: 10.1016/j.lfs.2022.120463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023]
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26
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Li H, Chen J, Liu J, Lai Y, Huang S, Zheng L, Fan N. CPT2 downregulation triggers stemness and oxaliplatin resistance in colorectal cancer via activating the ROS/Wnt/β-catenin-induced glycolytic metabolism. Exp Cell Res 2021; 409:112892. [PMID: 34688609 DOI: 10.1016/j.yexcr.2021.112892] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/18/2021] [Accepted: 10/20/2021] [Indexed: 01/05/2023]
Abstract
Carnitine palmitoyltransferase 2 (CPT2) has been demonstrated to act as a tumor promotor or suppressor in different types of cancers. However, little is known about the effect of CPT2 on colorectal cancer (CRC). In the present study, we analyzed CPT2 expression in CRC tissues and cells. CPT2 was overexpressed in CRC cell lines (SW480 and RKO), and its effects and molecular mechanism on the proliferation, glycolysis, stemness, and oxaliplatin sensitivity were investigated. The xenograft experiment was used to confirm the influence of CPT2 on CRC tumorigenesis in vivo. We found that CPT2 expression was significantly downregulated in CRC patients, and its lower expression was associated with the poor prognosis, large tumor size, advanced TNM stage, and poor histological grade differentiation of patients. Upregulation of CPT2 significantly inhibited the proliferation, glycolytic metabolism, cancer stem cell properties, and oxaliplatin resistance in CRC cells. Also, the increase of CPT2 inhibited tumorigenesis, stemness and glycolysis, while enhanced oxaliplatin sensitivity in mouse models. Mechanistically, CPT2 functioned via suppressing the activation of Wnt/β-catenin pathway through repressing ROS production. In conclusion, our results demonstrated that CPT2 was decreased in CRC, and CPT2 downregulation could trigger stemness and oxaliplatin resistance in CRC via activating the ROS/Wnt/β-catenin-induced glycolytic metabolism. This study indicates that CPT2 is a potential therapeutic target for CRC.
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Affiliation(s)
- Hui Li
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - JuHui Chen
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - Jie Liu
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - Yiqin Lai
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - Sha Huang
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - Liang Zheng
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China
| | - Nanfeng Fan
- Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China.
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27
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Dadgar T, Ebrahimi N, Gholipour AR, Akbari M, Khani L, Ahmadi A, Hamblin MR. Targeting the metabolism of cancer stem cells by energy disruptor molecules. Crit Rev Oncol Hematol 2021; 169:103545. [PMID: 34838705 DOI: 10.1016/j.critrevonc.2021.103545] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/17/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) have been identified in various tumor types. CSCs are believed to contribute to tumor metastasis and resistance to conventional therapy. So targeting these cells could be an effective strategy to eliminate tumors and a promising new type of cancer treatment. Alterations in metabolism play an essential role in CSC biology and their resistance to treatment. The metabolic properties pathways in CSCs are different from normal cells, and to some extent, are different from regular tumor cells. Interestingly, CSCs can use other nutrients for their metabolism and growth. The different metabolism causes increased sensitivity of CSCs to agents that disrupt cellular homeostasis. Compounds that interfere with the central metabolic pathways are known as energy disruptors and can reduce CSC survival. This review highlights the differences between regular cancer cells and CSC metabolism and discusses the action mechanisms of energy disruptors at the cellular and molecular levels.
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Affiliation(s)
- Tahere Dadgar
- Department of Biology, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Nasim Ebrahimi
- Division of Genetics, Department of Cell and Molecular & Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Amir Reza Gholipour
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Maryam Akbari
- Department of Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Khani
- Department of Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Amirhossein Ahmadi
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, 75169, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
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28
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Alhasan BA, Gordeev SA, Knyazeva AR, Aleksandrova KV, Margulis BA, Guzhova IV, Suvorova II. The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy. MEMBRANES 2021; 11:858. [PMID: 34832087 PMCID: PMC8620939 DOI: 10.3390/membranes11110858] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 11/16/2022]
Abstract
Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy.
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Affiliation(s)
| | | | | | | | | | | | - Irina I. Suvorova
- Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia; (B.A.A.); (S.A.G.); (A.R.K.); (K.V.A.); (B.A.M.); (I.V.G.)
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29
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Brunel A, Bégaud G, Auger C, Durand S, Battu S, Bessette B, Verdier M. Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells. Cells 2021; 10:1330. [PMID: 34072080 PMCID: PMC8227744 DOI: 10.3390/cells10061330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/22/2022] Open
Abstract
Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.
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