COTI-2 suppresses the malignancy of bladder cancer by inducing apoptosis via the AMPK-mTOR signaling pathway

Document Type : Original Article

Authors

1 Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China

2 Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

3 Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

4 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325000, China

5 The First Clinical Medical College of Wenzhou Medical University, Wenzhou, 325000, China

10.22038/ijbms.2024.80284.17378

Abstract

Objective(s): COTI-2, an innovative oral homocysteine, has shown promising antitumor results on multiple types of cancer. However, its effects in treating bladder cancer (BCa) and the underlying molecular mechanisms have not been elucidated. The present study aimed to explore the antitumor effects of COTI-2 on BCa and the potential mechanisms.
Materials and Methods: BCa cell lines, including the 5637 and T24 cell lines, were treated with COTI-2 at concentrations of 0.5 and 1 μM, respectively. Cell Counting Kit (CCK)-8 assay, colony formation assay, apoptosis assay, and transwell migration and invasion assay were conducted to evaluate the antitumor effects of COTI-2 on BCa cells. Western blotting, H&E, immunohistochemical staining, and immunofluorescence analysis were performed to investigate the underlying mechanisms. Moreover, a xenograft model in nude mice using T24 cells was generated to determine the antitumor activities of COTI-2 in vivo.
Results: COTI-2 highly inhibited the proliferation of BCa cell lines, including 5637 and T24 cells, and induced their apoptosis. Moreover, it efficiently suppressed the migration and invasion of BCa cells. Additionally, the subcutaneous xenograft model in nude mice showed that COTI-2 treatment inhibited the tumor growth of BCa by inducing its apoptosis in vivo. We also found that COTI-2 promoted apoptosis in BCa cells, presumably through activating the AMPK/mTOR pathway.
Conclusion: Our data suggest that COTI-2 effectively reduces the malignancy of BCa, probably by inducing apoptosis via the AMPK/mTOR signaling pathway. These data highlight the potential of COTI-2 as a therapeutic agent for the treatment of BCa. 

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Main Subjects

References

1. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol 2017; 71: 96-108.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424.
3. Gerber DE. Targeted therapies: A new generation of cancer treatments. Am Fam Physician 2008; 77: 311-319.
4. Comperat E, Amin MB, Cathomas R, Choudhury A, De Santis M, Kamat A, et al. Current best practice for bladder cancer: A narrative review of diagnostics and treatments. Lancet 2022; 400: 1712-1721.
5. Morana O, Wood W, Gregory CD. The apoptosis paradox in cancer. Int J Mol Sci 2022; 23: 1328-1347.
6. Gregory CD, Ford CA, Voss JJ. Microenvironmental effects of cell death in malignant disease. Adv Exp Med Biol 2016; 930: 51-88.
7. Wang F, Wu H, Fan M, Yu R, Zhang Y, Liu J, et al. Sodium butyrate inhibits migration and induces ampk-mtor pathway-dependent autophagy and ros-mediated apoptosis via the mir-139-5p/bmi-1 axis in human bladder cancer cells. FASEB J 2020; 34: 4266-4282.
8. Sun Y, Berleth N, Wu W, Schlutermann D, Deitersen J, Stuhldreier F, et al. Fin56-induced ferroptosis is supported by autophagy-mediated gpx4 degradation and functions synergistically with mtor inhibition to kill bladder cancer cells. Cell Death Dis 2021; 12: 1028-1042.
9. Keerthana CK, Rayginia TP, Shifana SC, Anto NP, Kalimuthu K, Isakov N, et al. The role of ampk in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment. Front Immunol 2023; 14: 1114582-1114597.
10. Luo Z, Zang M, Guo W. Ampk as a metabolic tumor suppressor: Control of metabolism and cell growth. Future Oncol 2010; 6: 457-470.
11. Gao D, Wang R, Gong Y, Yu X, Niu Q, Yang E, et al. Cab39 promotes cisplatin resistance in bladder cancer via the lkb1-ampk-lc3 pathway. Free Radic Biol Med 2023; 208: 587-601.
12. Huang Y, Zhou S, He C, Deng J, Tao T, Su Q, et al. Phenformin alone or combined with gefitinib inhibits bladder cancer via ampk and egfr pathways. Cancer Commun (Lond) 2018; 38: 50-63.
13. Kim LC, Cook RS, Chen J. Mtorc1 and mtorc2 in cancer and the tumor microenvironment. Oncogene 2017; 36: 2191-2201.
14. Populo H, Lopes JM, Soares P. The mtor signalling pathway in human cancer. Int J Mol Sci 2012; 13: 1886-1918.
15. Wang F, Cao M, Fan M, Wu H, Huang W, Zhang Y, et al. Ampk-mtor-ulk1 axis activation-dependent autophagy promotes hydroxycamptothecin-induced apoptosis in human bladder cancer cells. J Cell Physiol 2020; 235: 4302-4315.
16. Zhang Y, He N, Zhou X, Wang F, Cai H, Huang SH, et al. Betulinic acid induces autophagy-dependent apoptosis via bmi-1/ros/ampk-mtor-ulk1 axis in human bladder cancer cells. Aging (Albany NY) 2021; 13: 21251-21267.
17. Nagourney AJ, Gipoor JB, Evans SS, D’Amora P, Duesberg MS, Bernard PJ, et al. Therapeutic targeting of p53: A comparative analysis of apr-246 and coti-2 in human tumor primary culture 3-d explants. Genes (Basel) 2023; 14: 747-757.
18. Duffy MJ, Synnott NC, Crown J. Mutant p53 in breast cancer: Potential as a therapeutic target and biomarker. Breast Cancer Res Treat 2018; 170: 213-219.
19. Westin Shannon N, Wilberto Nieves-Neira Christian Lynam, Salim Kowthar Y, Silva Alison D, Ho Richard T, et al. Safety and early efficacy signals for COTI-2, an orally available small molecule targeting p53, in a phase I trial of recurrent gynecologic cancer. Cancer Res 2018; 78: 14-18.
20. Lindemann A, Patel AA, Silver NL, Tang L, Liu Z, Wang L, et al. Coti-2, a novel thiosemicarbazone derivative, exhibits antitumor activity in hnscc through p53-dependent and -independent mechanisms. Clin Cancer Res 2019; 25: 5650-5662.
21. Salim KY, Maleki Vareki S, Danter WR, Koropatnick J. Coti-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget 2016; 7: 41363-41379.
22. Al Hussein Al Awamlh B, Chang SS. Novel therapies for high-risk non-muscle invasive bladder cancer. Curr Oncol Rep 2023; 25: 83-91.
23. Martinez Rodriguez RH, Buisan Rueda O, Ibarz L. Bladder cancer: Present and future. Med Clin (Barc) 2017; 149: 449-455.
24. Synnott NC, O’Connell D, Crown J, Duffy MJ. Coti-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells. Breast Cancer Res Treat 2020; 179: 47-56.
25. Tang M, Crown J, Duffy MJ. Degradation of myc by the mutant p53 reactivator drug, coti-2 in breast cancer cells. Invest New Drugs 2023; 41: 541-550.
26. Perabo FG, Lindner H, Schmidt D, Huebner D, Blatter J, Fimmers R, et al. Preclinical evaluation of gemcitabine/paclitaxel-interactions in human bladder cancer lines. Anticancer Res 2003; 23: 4805-4814.
27. McKnight JJ, Gray SB, O’Kane HF, Johnston SR, Williamson KE. Apoptosis and chemotherapy for bladder cancer. J Urol 2005; 173: 683-690.
28. Wu P, Liu S, Su J, Chen J, Li L, Zhang R, et al. Apoptosis triggered by isoquercitrin in bladder cancer cells by activating the ampk-activated protein kinase pathway. Food Funct 2017; 8: 3707-3722.
29. Zhou X, Chen Y, Wang F, Wu H, Zhang Y, Liu J, et al. Artesunate induces autophagy dependent apoptosis through up-regulating ros and activating ampk-mtor-ulk1 axis in human bladder cancer cells. Chem Biol Interact 2020; 331: 109273.
30. Villanueva-Paz M, Cotan D, Garrido-Maraver J, Oropesa-Avila M, de la Mata M, Delgado-Pavon A, et al. Ampk regulation of cell growth, apoptosis, autophagy, and bioenergetics. Exp Suppl 2016; 107: 45-71.
31. Penugurti V, Mishra YG, Manavathi B. Ampk: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene. Biochim Biophys Acta Rev Cancer 2022; 1877: 188785.
32. Trefts E, Shaw RJ. Ampk: Restoring metabolic homeostasis over space and time. Mol Cell 2021; 81: 3677-3690.
33. Visnjic D, Dembitz V, Lalic H. The role of ampk/mtor modulators in the therapy of acute myeloid leukemia. Curr Med Chem 2019; 26: 2208-2229.
34. Ke H, Wang X, Zhou Z, Ai W, Wu Z, Zhang Y. Effect of weimaining on apoptosis and caspase-3 expression in a breast cancer mouse model. J Ethnopharmacol 2021; 264: 113363.
35. Xie Y, Lei X, Zhao G, Guo R, Cui N. Mtor in programmed cell death and its therapeutic implications. Cytokine Growth Factor Rev 2023; 71-72: 66-81.
36. Deutsch A, Leboeuf NR, Lacouture ME, McLellan BN. Dermatologic adverse events of systemic anticancer therapies: Cytotoxic chemotherapy, targeted therapy, and immunotherapy. Am Soc Clin Oncol Educ Book 2020; 40: 485-500.
37. Zhang Y, Li Y, Fu Q, Han Z, Wang D, Umar Shinge SA, et al. Combined immunotherapy and targeted therapies for cancer treatment: Recent advances and future perspectives. Curr Cancer Drug Targets 2023; 23: 251-264.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 3
March 2025
Pages 340-346

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