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Shi C, Ma X, Zhang R, Lin Z, Zhou X. The synergistic antitumour effect of Carrimycin combined with 5-fluorouracil on colorectal cancer. Sci Rep 2025; 15:9155. [PMID: 40097541 PMCID: PMC11914086 DOI: 10.1038/s41598-025-94306-5] [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: 01/13/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025] Open
Abstract
5-Fluorouracil (5-FU)-based chemotherapy often leads to drug resistance and adverse reactions in individuals with colorectal cancer (CRC). Carrimycin (CAM), a drug with notable antitumour effects across various tumour types, including hepatocellular carcinoma, glioblastoma, and small-cell lung carcinoma, offers an alternative owing to its limited side effects. Combination therapy is a common strategy to mitigate the negative effects of 5-FU and enhance its therapeutic efficacy. This study aimed to investigate the potential synergistic antitumour effects of CAM and 5-FU on HCT-15 and HT-29 CRC cell lines. Using computational analysis, we identified and quantified the synergistic effects of CAM and 5-FU. The combination therapy significantly outperformed 5-FU alone in inhibiting cell proliferation, colony formation, cell cycle progression, and migration. Additionally, it markedly increased the levels of reactive oxygen species and induced DNA damage. Furthermore, RNA-seq analysis revealed that the JNK and p38 MAPK signalling pathways were activated by this combination. In addition, the synergistic effects of the combination therapy were validated in a mouse subcutaneous tumour graft model. In conclusion, CAM enhances the sensitivity of CRC cells to 5-FU both in vitro and in vivo, suggesting its potential as a promising candidate for combination cancer therapy.
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Affiliation(s)
- Chaoyue Shi
- Central Laboratory, Yanbian University Hospital, Yanji, Jilin, China
| | - Xiao Ma
- Central Laboratory, Yanbian University Hospital, Yanji, Jilin, China
| | - Ruixue Zhang
- Central Laboratory, Yanbian University Hospital, Yanji, Jilin, China
| | - Zhenhua Lin
- Central Laboratory, Yanbian University Hospital, Yanji, Jilin, China
| | - Xianchun Zhou
- Central Laboratory, Yanbian University Hospital, Yanji, Jilin, China.
- Yanbian University Hospital, Yanji, 133000, Jilin Province, China.
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Wang Z, Cheng J, Wen H, Hou T, Luo F, Wang Y, Xu X, Liu Y, Zhao Y, Liang X. Synthesis, anticancer and antibacterial evaluation of novel spiramycin-acylated derivatives. RSC Adv 2024; 14:38898-38907. [PMID: 39654915 PMCID: PMC11626521 DOI: 10.1039/d4ra03126a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 10/28/2024] [Indexed: 12/12/2024] Open
Abstract
Spiramycin and its derivatives are commonly used antimicrobials, and its derivative, carrimycin, has recently been found to have good anticancer potential. Here, we found that the 4''-OH of spiramycin can be selectively acylated, resulting in a series of novel spiramycin derivatives with a structure similar to carrimycin. Anticancer studies showed that most of the derivatives exhibited moderate to good anti-proliferative activity against four cancer cell lines, including HGC-27, HT-29, HCT-116 and HeLa, especially compound 14, which has the strongest activity against HGC-27 cells with an IC50 value of 0.19 ± 0.02 μM. Pharmacological studies on HGC-27 cells revealed that compound 14 could arrest the cell cycle in the S phase, raise ROS levels, and induce cell apoptosis via activation of Erk/p38 MAPK signaling pathways. In addition, antibacterial studies showed that most of the spiramycin I derivatives modified at the 4''-OH group enhanced antibacterial activity on the four tested strains, including S. aureus, S. aureus MRSA, S. epidermidis, and B. subtilis. In particular, compound 16 was the most effective one and comparable to linezolid, a commonly used first-line antimicrobial. These results suggest that spiramycin I derivatives may provide an opportunity to design new anticancer or antibacterial agents, even dual-function agents.
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Affiliation(s)
- Zhiwei Wang
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Junxiang Cheng
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Hui Wen
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Tao Hou
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Fengbin Luo
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Yaodong Wang
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Xingjun Xu
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Yanfang Liu
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Yaopeng Zhao
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
| | - Xinmiao Liang
- Key Lab of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, CAS Dalian 116023 China +86 411 84379539 +86 411 84379519
- Ganjiang Chinese Medicine Innovation Center Nanchang 330000 China
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Xu Y, Gu X, Shan S, Liu Z, Wang S, Zhang J, Lei Y, Zhong C, Zheng Q, Ren T, Li Z. Isovalerylspiramycin I suppresses small cell lung cancer proliferation via ATR/CHK1 mediated DNA damage response and PERK/eIF2α/ATF4/CHOP mediated ER stress. Biochem Pharmacol 2024; 230:116557. [PMID: 39353535 DOI: 10.1016/j.bcp.2024.116557] [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: 05/08/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Small cell lung cancer (SCLC) urgently needs new therapeutic approaches. We found that the antibiotic-derived compound Isovalerylspiramycin I (ISP-I) has potent anti-tumor activity against SCLC cell lines H1048 and DMS53 both in vitro and in vivo. ISP-I induced apoptosis, G2/M phase cell cycle arrest, and mitochondrial respiratory chain dysfunction in both cell lines. Comprehensive RNA sequencing revealed that the anti-SCLC effects of ISP-I were primarily attributed to ATR/CHK1-mediated DNA damage response and PERK/eIF2α/ATF4/CHOP-mediated ER stress. Importantly, the induction of DNA damage, ER stress, and apoptosis by ISP-I was mitigated by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), underscoring the critical role of ROS in the anti-SCLC mechanism of ISP-I. Moreover, ISP-I treatment induced immunogenic cell death (ICD) in SCLC cells, as evidenced by increased adenosine triphosphate (ATP) secretion, elevated release of high-mobility group box 1 (HMGB1), and enhanced exposure of calreticulin (CRT) on the cell surface. Additionally, network pharmacology analysis, combined with cellular thermal shift assay (CETSA) and cycloheximide (CHX) chase experiments, demonstrated that ISP-I acted as a ligand for apurinic/apyrimidinic endonuclease 1 (APEX1) and promoted its degradation, leading to the accumulation of ROS. In conclusion, our findings elucidate the multifaceted mechanisms underlying the anti-cancer effects of ISP-I, highlighting its potential as a promising therapeutic candidate for SCLC treatment.
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Affiliation(s)
- Yongle Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Xiaohua Gu
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Shan Shan
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Zeyu Liu
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Shaoyang Wang
- School of Biomedical Engineering, Hainan University, Haikou 570228, China.
| | - Jingyuan Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yuqiong Lei
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Cheng Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Qi Zheng
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Tao Ren
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Zhanxia Li
- Department of Respiratory and Critical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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Yang X, Shen Y, Hu T, Li H, Zhang Y, Shen Y, Wu D. Carrimycin in a Patient with Acute Myeloid Leukemia Complicated with Life-Threatening Mixed Perianal Infection: A Case Report and Literature Review. Infect Drug Resist 2024; 17:3637-3642. [PMID: 39184012 PMCID: PMC11345016 DOI: 10.2147/idr.s475982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 08/09/2024] [Indexed: 08/27/2024] Open
Abstract
Background Perianal infection has a high incidence and mortality rate in patients with acute myeloid leukemia (AML). Sometimes there is a lack of effective anti-infective treatment regimens. Case Presentation A 58-year-old male diagnosed with AML presented with secondary perianal infection and septic shock upon admission. Although multiple pathogen cultivation and antibiotic sensitivity tests indicated the presence of sensitive strains, the corresponding antibiotics were ineffective. As a last resort, carrimycin was introduced, ultimately controlling the infection and leading to disease remission. Conclusion Carrimycin is a complementary treatment option when conventional antibiotic therapy fails. It operates through multiple mechanisms beyond its antibiotic properties and warrants further investigation.
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Affiliation(s)
- Xiawan Yang
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Yingying Shen
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Tonglin Hu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Hangchao Li
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Yun Zhang
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Yiping Shen
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
| | - Dijiong Wu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
- National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China
- Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China
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Du N, You D, Tenzing D, Qu D, Meng J, Wang Y, He J. Carrimycin, as One of the Drugs in Combination Therapy, for the Treatment of Carbapenem-Resistant Acinetobacter Baumannii Infection. Infect Drug Resist 2024; 17:3617-3621. [PMID: 39184014 PMCID: PMC11342940 DOI: 10.2147/idr.s468413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 08/09/2024] [Indexed: 08/27/2024] Open
Abstract
Purpose Infection with carbapenem-resistant Acinetobacter baumannii (CRAB) is a tough nut to crack. Carrimycin is a novel recombinant macrolide antibiotic, and has good anti-infection effects in vivo. At present, it is rarely reported for treatment of CRAB infection. We present a case where a patient with COVID-19 complicated by CRAB infection was successfully treated with a combination therapy including carrimycin, offering clinical insights and experience. Patients and Methods The patient infected with CRAB was cured by carrimycin combined with tigecycline and amikacin ultimately. We analyzed and summarized the therapeutic regimen and disease feature to provide reference for clinical treatment. Results The patient was admitted to emergency observation wards with fever and was diagnosed with COVID-19 pneumonia. During the treatment, his condition worsened. He had a fever, cough, and expectoration. After 3 days of empirical treatment with meropenem, tested positive for A. baumannii infection by the next-generation sequencing, and CRAB was detected in blood and sputum culture. Then, he was administered with tigecycline and amikacin immediately for 5 days, however the therapeutic effect was not significant. The patient still remained in a high inflammatory response. Ultimately, the treatment regimen was changed to carrimycin combined with tigecycline and amikacin for 7 days, and then carrimycin combined with tigecycline for 10 days, the patient's clinical condition gradually improved. The patient received carrimycin monotherapy for 7 days, then discharged. Conclusion Carrimycin may be a bright alternative for CRAB infection as one of the drugs in combination therapy, especially in a patient with hyperinflammatory response.
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Affiliation(s)
- Ning Du
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong Province, People’s Republic of China
| | - Dan You
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihar, Heilongjiang Province, People’s Republic of China
| | - Dava Tenzing
- Department of Emergency, People’s Hospital of Shigatse City, Shigatse, Xizang Autonomous Region, People’s Republic of China
| | - Dongxiang Qu
- Department of Pharmacy, The First Hospital of Qiqihar, Qiqihar, Heilongjiang Province, People’s Republic of China
| | - Jun Meng
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong Province, People’s Republic of China
| | - Yihui Wang
- Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Juan He
- Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
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Zhao X, Leng D, Wang H, Jin H, Wu Y, Qin Z, Wu D, Wei X. An Acid-Responsive Iron-Based Nanocomposite for OSCC Treatment. J Dent Res 2024; 103:612-621. [PMID: 38684484 DOI: 10.1177/00220345241238154] [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] [Indexed: 05/02/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, characterized by invasiveness, local lymph node metastasis, and poor prognosis. Traditional treatment and medications have limitations, making the specific inhibition of OSCC growth, invasion, and metastasis a challenge. The tumor microenvironment exhibits mildly acidity and high concentrations of H2O2, and its exploitation for cancer treatment has been widely researched across various cancers, but research in the oral cancer field is relatively limited. In this study, by loading ultra-small Prussian blue nanoparticles (USPBNPs) into mesoporous calcium-silicate nanoparticles (MCSNs), we developed an acid-responsive iron-based nanocomposite, USPBNPs@MCSNs (UPM), for the OSCC treatment. UPM demonstrated excellent dual enzyme activities, generating toxic ·OH in a mildly acidic environment, effectively killing OSCC cells and producing O2 in a neutral environment to alleviate tissue hypoxia. The results showed that UPM could effectively inhibit the proliferation, migration, and invasion of OSCC cells, as well as the growth of mice solid tumors, without obvious systemic toxicity. The mechanisms may involve UPM inducing ferroptosis of OSCC cells by downregulating the xCT/GPX4/glutathione (GSH) axis, characterized by intracellular iron accumulation, reactive oxygen species accumulation, GSH depletion, lipid peroxidation, and abnormal changes in mitochondrial morphology. Therefore, this study provides empirical support for ferroptosis as an emerging therapeutic target for OSCC and offers a valuable insight for future OSCC treatment.
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Affiliation(s)
- X Zhao
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - D Leng
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - H Wang
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - H Jin
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Y Wu
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Z Qin
- Nanjing Medical University, The First Clinical Medical College, Jiangsu Province Hospital, Nanjing, Jiangsu, China
| | - D Wu
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - X Wei
- Jiangsu Province Key Laboratory of Oral Diseases & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine & Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
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Cui XQ, Zhang LW, Zhao P, Feng JJ. Efficacy and safety of carrimycin in ten patients with severe pneumonia following solid organ transplantation. World J Clin Cases 2024; 12:2542-2550. [PMID: 38817218 PMCID: PMC11135438 DOI: 10.12998/wjcc.v12.i15.2542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/24/2024] [Accepted: 03/28/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND The number of patients undergoing solid organ transplantation has increased annually. However, infections in solid organ transplant recipients can have a severe effect on patient survival owing to the continued use of immunosuppressants. Carrimycin is a novel macrolide antibiotic produced by genetically engineered streptomyces spiramyceticus harboring a 4''-O-isovaleryltransferase gene (ist) from streptomyces thermotoleran. Carrimycin has good antibacterial and antiviral effects. However, no relevant studies have been conducted on the efficacy and safety of carrimycin in patients with severe pneumonia (SP) after solid organ transplantation. AIM To explore the efficacy and safety of carrimycin in patients with SP after solid organ transplantation to provide a medication reference for clinical treatment. METHODS In March 2022, ten patients with SP following solid-organ transplantation were treated at our hospital between January 2021 and March 2022. When the condition was critical and difficult to control with other drugs, carrimycin was administered. These ten patients' clinical features and treatment protocols were retrospectively analyzed, and the efficacy and safety of carrimycin for treating SP following solid organ transplantation were evaluated. RESULTS All ten patients were included in the analysis. Regarding etiological agent detection, there were three cases of fungal pneumonia, two cases of bacterial pneumonia, two cases of Pneumocystis pneumonia, and three cases of mixed infections. After treatment with carrimycin, the disease in seven patients significantly improved, the course of the disease was significantly shortened, fever was quickly controlled, chest computed tomography was significantly improved, and oxygenation was significantly improved. Finally, the patients were discharged after curing. One patient died of acute respiratory distress syndrome, and two patients discontinued treatment. CONCLUSION Carrimycin is a safe and effective treatment modality for SP following solid organ transplantation. Carrimycin may have antibacterial and antiviral effects in patients with SP following solid organ transplantation.
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Affiliation(s)
- Xian-Quan Cui
- Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Lu-Wei Zhang
- Department of Blood Purification, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Peng Zhao
- Department of Organ Transplantation, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jing-Jing Feng
- Department of Blood Purification, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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Lai J, Liang J, Chen K, Guan B, Chen Z, Chen L, Fan J, Zhang Y, Li Q, Su J, Chen Q, Lin J. Carrimycin ameliorates lipopolysaccharide and cecal ligation and puncture-induced sepsis in mice. Chin J Nat Med 2024; 22:235-248. [PMID: 38553191 DOI: 10.1016/s1875-5364(24)60600-x] [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: 07/14/2023] [Indexed: 04/02/2024]
Abstract
Carrimycin (CA), sanctioned by China's National Medical Products Administration (NMPA) in 2019 for treating acute bronchitis and sinusitis, has recently been observed to exhibit multifaceted biological activities, encompassing anti-inflammatory, antiviral, and anti-tumor properties. Despite these applications, its efficacy in sepsis treatment remains unexplored. This study introduces a novel function of CA, demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in mice models. Our research employed in vitro assays, real-time quantitative polymerase chain reaction (RT-qPCR), and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6), in response to LPS stimulation. Additionally, Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B (NF-κB) activation in LPS-stimulated RAW264.7 cells. Complementing these findings, in vivo experiments demonstrated that CA effectively alleviates LPS- and CLP-triggered organ inflammation in C57BL/6 mice. Further insights were gained through 16S sequencing, highlighting CA's pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways, particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP. Notably, a comparative analysis revealed that CA's anti-inflammatory efficacy surpasses that of equivalent doses of aspirin (ASP) and TIENAM. Collectively, these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment. This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.
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Affiliation(s)
- Junzhong Lai
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Jiadi Liang
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Kunsen Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Biyun Guan
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Zhirong Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Linqin Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Jiqiang Fan
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Yong Zhang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Qiumei Li
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Jingqian Su
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, Fujian Normal University, Fuzhou 350117, China.
| | - Jizhen Lin
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou 350001, China; The Department of Otolaryngology, Head & Neck Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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Yang FY, Shao L, Su J, Zhang ZM. Carrimycin in the treatment of acute promyelocytic leukemia combined with pulmonary tuberculosis: A case report. World J Clin Cases 2024; 12:623-629. [PMID: 38322455 PMCID: PMC10841942 DOI: 10.12998/wjcc.v12.i3.623] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/17/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Pulmonary tuberculosis (PTB) is prevalent in immunocompromised populations, including patients with hematologic malignancies, human immunodeficiency virus infections, and chronic diseases. Effective treatment for acute promyelocytic leukemia (APL) combined with PTB is lacking. These patients show an extremely poor prognosis. Therefore, studies should establish efficient treatment options to improve patient survival and prognosis. CASE SUMMARY A 60-year-old male with pain in the right side of his chest and a fever for 4 d visited the outpatient department of our hospital. Peripheral blood smear revealed 54% blasts. Following bone marrow examinations, variant APL with TNRC18-RARA fusion gene was diagnosed. Chest computed tomography scan showed bilateral pneumonitis with bilateral pleural effusions, partial atelectasis in the lower lobes of both lungs, and the bronchoalveolar lavage fluid gene X-Pert test was positive, indicative of PTB. Carrimycin, ethambutol (EMB), and isoniazid (INH) were administered since he could not receive chemotherapy as the WBC count decreased continuously. After one week of treatment with carrimycin, the patient recovered from fever and received chemotherapy. Chemotherapy was very effective and his white blood cells counts got back to normal. After being given five months with rifampin, EMB and INH and chemotherapy, the patient showed complete remission from pneumonia and APL. CONCLUSION We report a case of PTB treated successfully with carrimycin with APL that requires chemotherapy.
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Affiliation(s)
- Fu-Yu Yang
- Department of Infectious Diseases, The Affiliated Central Hospital of Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Lei Shao
- Department of Infectious Diseases, The Affiliated Central Hospital of Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Jie Su
- Department of Infectious Diseases, The Affiliated Central Hospital of Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Zhen-Meng Zhang
- Department of Infectious Diseases, The Affiliated Central Hospital of Shandong First Medical University, Jinan 250013, Shandong Province, China
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10
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Li S, Wang A, Wu Y, He S, Shuai W, Zhao M, Zhu Y, Hu X, Luo Y, Wang G. Targeted therapy for non-small-cell lung cancer: New insights into regulated cell death combined with immunotherapy. Immunol Rev 2024; 321:300-334. [PMID: 37688394 DOI: 10.1111/imr.13274] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/10/2023]
Abstract
Non-small-cell lung cancer (NSCLC), which has a high rate of metastatic spread and drug resistance, is the most common subtype of lung cancer. Therefore, NSCLC patients have a very poor prognosis and a very low chance of survival. Human cancers are closely linked to regulated cell death (RCD), such as apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Currently, small-molecule compounds targeting various types of RCD have shown potential as anticancer treatments. Moreover, RCD appears to be a specific part of the antitumor immune response; hence, the combination of RCD and immunotherapy might increase the inhibitory effect of therapy on tumor growth. In this review, we summarize small-molecule compounds used for the treatment of NSCLC by focusing on RCD and pharmacological systems. In addition, we describe the current research status of an immunotherapy combined with an RCD-based regimen for NSCLC, providing new ideas for targeting RCD pathways in combination with immunotherapy for patients with NSCLC in the future.
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Affiliation(s)
- Shutong Li
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Aoxue Wang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yongya Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Shengyuan He
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Wen Shuai
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Min Zhao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yumeng Zhu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Xiuying Hu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
| | - Guan Wang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology & Immunology, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, China
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11
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Nan C, Zhang X, Huang W, Zhu B, Zhao J, Lu S, Xian L, Liu K, Ma G, Yang W, Huang M, Zhou D, Zhang M, Duan Y, Wu G, Jiang Z, Zhang L, He X, Chen Y, Xing X, Wang C, Wang D, Yu K. Effects of carrimycin on biomarkers of inflammation and immune function in tumor patients with sepsis: A multicenter double-blind randomized controlled trial. Pharmacol Res 2023; 198:106991. [PMID: 37984505 DOI: 10.1016/j.phrs.2023.106991] [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: 09/26/2023] [Revised: 10/30/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023]
Abstract
Carrimycin is a potential immune-regulating agent for sepsis in patients with tumors. In this study, we investigated its effects on inflammation and immune function in tumor patients with sepsis. In total, 120 participants were randomized to receive either carrimycin treatment (400 mg/day) (n = 62) or placebo (n = 58) for 7 days. The primary outcomes were immune-related indicators. Subsequently, patients were stratified into two subgroups (CD4 < 38.25% and CD8 < 25.195%). Ninety-nine participants were analyzed: 47 and 52 in the carrimycin and placebo groups, respectively. HLA-DR levels were rapidly increased in the carrimycin group; however, the placebo group initially experienced a decline in HLA-DR level at 1 day after administration. In the subgroup with CD4 < 38.25%, the carrimycin group exhibited significantly higher HLA-DR levels than the placebo group (2.270, P = 0.023) 1 day after administration and the degree of increase in HLA-DR in the carrimycin group was higher than that in the placebo group (2.057, P = 0.040). In the CD8 < 25.195% subgroup, the carrimycin group demonstrated significantly higher levels of CD8+ T cells than the placebo group at 3 (2.300,P = 0.027) and 5 (2.106, P = 0.035) days after administration. Carrimycin intervention led to significant reductions in the SOFA, APACHE II, PCT, and CRP levels. No adverse events were observed. In tumor patients with sepsis, particularly in those experiencing immunological suppression, carrimycin effectively regulates immune responses by increasing HLA-DR and CD8+ T cell levels and plays an anti-infective role, reducing disease severity. (Chictr.org.cn, ID Number: ChiCTR2000032339).
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Affiliation(s)
- Chuanchuan Nan
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin 150001, China; Department of Critical Care Medicine, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518000, China
| | - Xiaowu Zhang
- Department of Critical Care Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wei Huang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin 150001, China
| | - Biao Zhu
- Department of Critical Care Medicine, Shanghai Cancer Center of Fudan University, Shanghai 200032, China
| | - Jianghong Zhao
- Department of Critical Care Medicine, Hunan Cancer Hospital, Changsha 410013, China
| | - Song Lu
- Department of Critical Care Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Lewu Xian
- Department of Critical Care Medicine, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510000, China
| | - Kaizhong Liu
- Department of Critical Care Medicine, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310022, China
| | - Gang Ma
- Department of Critical Care Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510000, China
| | - Wei Yang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Mingguang Huang
- Department of Critical Care Medicine, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030000, China
| | - Dongmin Zhou
- Department of Critical Care Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Ming Zhang
- Department of Critical Care Medicine, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310022, China
| | - Yan Duan
- Department of Critical Care Medicine, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030000, China
| | - Guixin Wu
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, Chongqing 404100, China
| | - Zhengying Jiang
- Department of Critical Care Medicine, Chongqing University Cancer Hospital, Chongqing 404100, China
| | - Li Zhang
- Department of Critical Care Medicine, Hubei Cancer Hospital, Wuhan 430079, China
| | - Xinrong He
- Department of Critical Care Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510000, China
| | - Yuhong Chen
- Department of Critical Care Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Xuezhong Xing
- Department of Critical Care Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100000, China
| | - Changsong Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin 150001, China.
| | - Donghao Wang
- Department of Critical Care Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
| | - Kaijiang Yu
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
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12
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Dardashti RN, Laps S, Gichtin JS, Metanis N. The semisynthesis of nucleolar human selenoprotein H. Chem Sci 2023; 14:12723-12729. [PMID: 38020378 PMCID: PMC10646972 DOI: 10.1039/d3sc03059h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
The human selenoprotein H is the only selenocysteine-containing protein that is located in the cell's nucleolus. In vivo studies have suggested that it plays some role in DNA binding, consumption of reactive oxygen species, and may serve as a safeguard against cancers. However, the protein has never been isolated and, as a result, not yet fully characterized. Here, we used a semi-synthetic approach to obtain the full selenoprotein H with a S43T mutation. Using biolayer interferometry, we also show that the Cys-containing mutant of selenoprotein H is capable of binding DNA with sub-micromolar affinity. Employing state-of-the-art expressed protein ligation (EPL), our devised semi-synthetic approach can be utilized for the production of numerous, hard-to-obtain proteins of biological and therapeutic relevance.
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Affiliation(s)
- Rebecca Notis Dardashti
- The Institute of Chemistry, The Hebrew University of Jerusalem Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
| | - Shay Laps
- The Institute of Chemistry, The Hebrew University of Jerusalem Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
| | - Jacob S Gichtin
- The Institute of Chemistry, The Hebrew University of Jerusalem Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
| | - Norman Metanis
- The Institute of Chemistry, The Hebrew University of Jerusalem Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
- Casali Center for Applied Chemistry, The Hebrew University of Jerusalem Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
- The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat Ram Jerusalem 9190401 Israel
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13
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Li XY, Luo YT, Wang YH, Yang ZX, Shang YZ, Guan QX. Anti-inflammatory effect and antihepatoma mechanism of carrimycin. World J Gastroenterol 2023; 29:2134-2152. [PMID: 37122599 PMCID: PMC10130968 DOI: 10.3748/wjg.v29.i14.2134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/29/2022] [Accepted: 03/09/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND New drugs are urgently needed for the treatment of liver cancer, a feat that could be feasibly accomplished by finding new therapeutic purposes for marketed drugs to save time and costs. As a new class of national anti-infective drugs, carrimycin (CAM) has strong activity against gram-positive bacteria and no cross resistance with similar drugs. Studies have shown that the components of CAM have anticancer effects. AIM To obtain a deeper understanding of CAM, its distribution, metabolism and anti-inflammatory effects were assessed in the organs of mice, and its mechanism of action against liver cancer was predicted by a network pharmacology method. METHODS In this paper, the content of isovaleryl spiramycin III was used as an index to assess the distribution and metabolism of CAM and its effect on inflammatory factors in various mouse tissues and organs. Reverse molecular docking technology was utilized to determine the target of CAM, identify each target protein based on disease type, and establish a target protein-disease type network to ascertain the effect of CAM in liver cancer. Then, the key action targets of CAM in liver cancer were screened by a network pharmacology method, and the core targets were verified by molecular docking and visual analyses. RESULTS The maximum CAM concentration was reached in the liver, kidney, lung and spleen 2.5 h after intragastric administration. In the intestine, the maximum drug concentration was reached 0.5 h after administration. In addition, CAM significantly reduced the interleukin-4 (IL-4) levels in the lung and kidney and especially the liver and spleen; moreover, CAM significantly reduced the IL-1β levels in the spleen, liver, and kidney and particularly the small intestine and lung. CAM is predicted to regulate related pathways by acting on many targets, such as albumin, estrogen receptor 1, epidermal growth factor receptor and caspase 3, to treat cancer, inflammation and other diseases. CONCLUSION We determined that CAM inhibited inflammation. We also predicted the complex multitargeted effects of CAM that involve multiple pathways and the diversity of these effects in the treatment of liver cancer, which provides a basis and direction for further clinical research.
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Affiliation(s)
- Xiu-Yan Li
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Yu-Ting Luo
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Yan-Hong Wang
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Zhi-Xin Yang
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Yu-Zhou Shang
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Qing-Xia Guan
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
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14
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Yu LC, Dang DD, Zhuang S, Chen S, Zhuang Z, Rosenblum JS. Carrimycin, a first in-class anti-cancer agent, targets selenoprotein H to induce nucleolar oxidative stress and inhibit ribosome biogenesis. CANCER PATHOGENESIS AND THERAPY 2023; 1:111-115. [PMID: 37750087 PMCID: PMC10518895 DOI: 10.1016/j.cpt.2022.12.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity; however, its exact mechanism of action and molecular target were previously unknown. It was recently elucidated that Isovalerylspiramycin I (ISP I), the active component of carrimycin, targets selenoprotein H (SelH), a nucleolar reactive oxygen species-scavenging enzyme in the selenoprotein family. ISP I treatment accelerates SelH degradation, resulting in oxidative stress, disrupted ribosomal biogenesis, and apoptosis in tumor cells. Specifically, ISP I disrupts the association between RNA polymerase I and ribosomal DNA in the nucleolus. This inhibits ribosomal RNA transcription and subsequent ribosomal assembly, which prevents cancer cells from sustaining elevated rates of protein synthesis and cellular proliferation that are necessary for tumor growth and malignancy. In this review, we (1) describe the historical categorization and evolution of anti-cancer agents, including macrolide antibiotics, (2) outline the discovery of SelH as a target of ISP I, and (3) summarize the ways in which carrimycin has been used both clinically and at the bench to date and propose additional potential therapeutic uses.
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Affiliation(s)
- LaYow C. Yu
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Danielle D. Dang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Sophie Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Shuran Chen
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Jared S. Rosenblum
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
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15
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Zhu W, Tian Y, Xiang L, Cao L, He L. A Case of Multidrug-Resistant Klebsiella pneumoniae Treated with Carrimycin. Infect Drug Resist 2023; 16:2365-2369. [PMID: 37113529 PMCID: PMC10126721 DOI: 10.2147/idr.s407076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
One of the most pressing emerging issues in bacterial resistance is multidrug-resistant Klebsiella pneumoniae. The treatment of K. pneumoniae infections is often problematic because of the lack of available therapeutic options, leading to negative effects on morbidity, mortality, and healthcare-associated costs. Carrimycin is a macrolide antibiotic with good antibacterial effects. In this study, we report a patient diagnosed with multidrug-resistant K. pneumoniae infection who was treated with carrimycin. The patient presented with cough, expectoration, dyspnea, and severe hypoxemia requiring noninvasive ventilation. We successively used a variety of antibiotics, including meropenem, tigecycline, and polymyxin, with unsatisfactory results. Finally, we used carrimycin, and the patient's condition improved, resulting in hospital discharge. Therefore, for patients with multidrug-resistant K. pneumoniae infection that does not respond to conventional anti-infective treatments, carrimycin can be considered a treatment option.
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Affiliation(s)
- Wenjun Zhu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Yaping Tian
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Lin Xiang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Linna Cao
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Lirong He
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
- Correspondence: Lirong He, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86 18170905103, Fax +86 0791 86311242, Email
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16
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Cui J, Zhou J, He W, Ye J, Westlake T, Medina R, Wang H, Thakur BL, Liu J, Xia M, He Z, Indig FE, Li A, Li Y, Weil RJ, Aladjem MI, Zhong L, Gilbert MR, Zhuang Z. Targeting selenoprotein H in the nucleolus suppresses tumors and metastases by Isovalerylspiramycin I. J Exp Clin Cancer Res 2022; 41:126. [PMID: 35387667 PMCID: PMC8985259 DOI: 10.1186/s13046-022-02350-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
Background Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells. Methods We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway. Results ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells. Conclusions We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02350-0.
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Liu Z, Huang M, Hong Y, Wang S, Xu Y, Zhong C, Zhang J, Zhuang Z, Shan S, Ren T. Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3K/AKT signaling pathway. Int J Biol Sci 2022; 18:3714-3730. [PMID: 35813464 PMCID: PMC9254468 DOI: 10.7150/ijbs.69989] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 05/10/2022] [Indexed: 11/24/2022] Open
Abstract
Novel drugs are required for non-small cell lung cancer (NSCLC) treatment urgently. Repurposing old drugs as new treatments is a practicable approach with time and cost savings. Some studies have shown that carrimycin, a Chinese Food and Drug Administration (CFDA)-approved macrolide antibiotic, possesses potent anti-tumor effects against oral squamous cell carcinoma. However, its detailed component and underlying mechanisms in anti-NSCLC remain unknown. In our study, isovalerylspiramycin I (ISP-I) was isolated from carrimycin and demonstrated a remarkable anti-NSCLC efficacy in vitro and in vivo with a favorable safety profile. It has been proven that in NSCLC cell lines H460 and A549, ISP-I could induce G2/M arrest and apoptosis, which was mainly attributed to ROS accumulation and subsequently PI3K/AKT signaling pathway inhibition. Numerous downstream genes including mTOR and FOXOs were also changed correspondingly. An observation of NAC-induced reverse effect on ISP-I-leading cell death and PI3K/AKT pathway inhibition, emphasized the necessity of ROS signaling in this event. Moreover, we identified ROS accumulation and PI3K/AKT pathway inhibition in tumor xenograft models in vivo as well. Taken together, our study firstly reveals that ISP-I is a novel ROS inducer and may act as a promising candidate with multi-target and low biological toxicity for anti-NSCLC treatment.
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Affiliation(s)
- Zeyu Liu
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Moli Huang
- Department of Bioinformatics, School of Biological and Basic Medical Sciences, Soochow University, Suzhou, 215123, China
| | - Yue Hong
- Stem Cell Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Shaoyang Wang
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yongle Xu
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Cheng Zhong
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jingyuan Zhang
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Zhengping Zhuang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shan Shan
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Tao Ren
- Department of Respiratory and Clinical Care Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
- Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
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18
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Jin Y, Zuo HX, Li MY, Zhang ZH, Xing Y, Wang JY, Ma J, Li G, Piao H, Gu P, Jin X. Anti-Tumor Effects of Carrimycin and Monomeric Isovalerylspiramycin I on Hepatocellular Carcinoma in Vitro and in Vivo. Front Pharmacol 2021; 12:774231. [PMID: 34899336 PMCID: PMC8662527 DOI: 10.3389/fphar.2021.774231] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 10/27/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma results in a high risk of second primary malignancies and has prominent morbidity and mortality. There is a lack of effective treatment and prognosis is poor. Therefore, effective drugs need to be discovered. Carrimycin is a 16-member macrolide antibiotic with anticancer activity, and monomeric isovalerylspiramycin I is a main component. The aim of this study was to determine the anti-tumor effects of carrimycin and monomeric isovalerylspiramycin I on hepatocellular carcinoma through in vivo and in vitro experiments. In vitro, changes in cellular proliferation, migration, invasion, and apoptosis were analyzed by MTT, colony formation, EdU labeling, wound-healing, matrigel transwell invasion, and flow cytometric assays using SK-Hep1, Hep3B, SNU-354, SNU-387 hepatocellular carcinoma cell lines. Western blotting and RT-PCR were used to detect the effects of carrimycin and monomeric isovalerylspiramycin I on the expression levels of vascular endothelial growth factor (VEGF) and programmed death ligand 1 (PD-L1). Nude mice were subcutaneously transplanted with SK-Hep1 cells or C57BL/6J mice were orthotopically transplanted with hepatocarcinoma H22 cells. Tumor volume, pathological changes in tumor tissues, and the concentration of VEGF in mouse serum were measured after treatments. Carrimycin and monomeric isovalerylspiramycin I dose-dependently inhibited hepatocellular carcinoma cell viability, colony formation, and DNA replication. These agents markedly suppressed migration and invasion and promoted apoptosis of the cell lines. Western blotting and RT-PCR demonstrated that carrimycin and monomeric isovalerylspiramycin I reduced VEGF and PD-L1 protein and mRNA levels in a dose-dependent manner. In vivo studies further confirmed that carrimycin and monomeric isovalerylspiramycin I could significantly inhibit tumor growth, tumor histopathological alterations, and the concentration of VEGF in both mouse tumor models. These results show that carrimycin and monomeric isovalerylspiramycin I promoted apoptosis and inhibited proliferation, migration, and invasion of hepatocellular carcinoma cells. Therefore, our discovery suggests anti-tumor capacity for carrimycin and monomeric isovalerylspiramycin I and provides data on potential new drugs for inhibiting hepatocellular carcinoma.
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Affiliation(s)
- Yong Jin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Hong Xiang Zuo
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Ming Yue Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Zhi Hong Zhang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Yue Xing
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Jing Ying Wang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Juan Ma
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Gao Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
| | - Hongxin Piao
- Liver Diseases Branch, Yanbian University Affiliated Hospital, Yanji, China
| | - Puqing Gu
- Shanghai Tonglian Pharmaceutical Co., Ltd, Shanghai, China
| | - Xuejun Jin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, China
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