Department of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa , jakudugu@sun.ac.za
Abstract: (175 Views)
Background:Single agent use of chemotherapy in prostate cancer is very limiting, as large doses are often required for tumour control and can lead to elevated systemic toxicity. Targeting of survival proteins of the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR) and androgen receptor (AR) pathways with cocktails of specific inhibitors might yield optimum therapeutic benefit with minimal toxicity. Materials & Methods: The modes of interaction of the dual inhibitor of PI3K and mTOR (NVP-BEZ235), EGFR inhibitor (AG-1478), and AR inhibitor (MDV3100) in in vitro cultures of four human prostate cell lines (DU145, LNCaP, BPH-1 and 1542N) were evaluated as cocktails, using clonogenic cell survival, subsequent to validation of the androgen dependency. Components of cocktails (Cocktail 1 (AG-1478 and NVP-BEZ235), Cocktail 2 (NVP-BEZ235 and MDV3100), and Cocktail 3 (MDV3100 and AG-1478)) were used at equivalent concentrations for 50% cell killing. Combination indices (CI) for the cocktails were determined and used as descriptors of inhibitor interaction. Radiomodulatory effects of inhibitor cocktails were also evaluated. Results: Inhibitor cocktails selectively showed strong to very strong synergism and radiosensitization. Concurrent inhibition of PI3K/mTOR and AR could potentially be of better therapeutic benefit than inhibition of EGFR and PI3K/mTOR or AR and EGFR, as the potential benefit of EGFR targeting was found to be limited. Conclusion: These data may guide the design of potent treatment approaches for prostate cancer.
1. Choudury AD (2022) PTEN-PI3K alterations in advanced prostate cancer and clinical implications. The Prostate, 82: S60-S72. [DOI:10.1002/pros.24372]
2. Maleka S, Serafin A, Hamunyela R, Hamid M, Achel D, Akudugu J (2015) NVP-BEZ235 enhances radiosensitivity of human prostate cancer cells but acts as a radioprotector to normal prostate cells. J Cancer Biol Therap, 1: 38-45. [DOI:10.18314/gjct.v1i1.32]
3. Akudugu JM and Slabbert JP (2008) Modulation of radiosensitivity in Chinese hamster lung fibroblasts by cisplatin. Can J Physiol Pharmacol, 86: 257-263. [DOI:10.1139/Y08-035]
4. Hamunyela RH, Serafin AM, Akudugu JM (2017) Strong synergism between small molecule inhibitors of HER2, PI3K, mTOR and Bcl-2 in human breast cancer cells. Toxicol In Vitro, 38: 117-123. [DOI:10.1016/j.tiv.2016.10.002]
5. Maleka S, Serafin AM, Akudugu JM (2019) PI3K and mTOR inhibitor, NVP-BEZ235, is more toxic than X-rays in prostate cancer cells. Int J Radiat Res, 17: 37-45.
6. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A (2016) 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med, 57: 1941-1944. [DOI:10.2967/jnumed.116.178673]
7. Di Donato M, Giovannelli P, Migliaccio A, Castoria G (2023) New approaches targeting the invasive phenotype of prostate cancer-associated fibroblasts. In Biology and Life Sciences Forum (Vol. 21, No. 1, p. 1). MDPI. [DOI:10.3390/blsf2023021001]
8. Lukashchuk N, Barnicle A, Adelman CA, Armenia J, Kang J, Barrett JC, Harrington EA (2023) Impact of DNA damage repair alterations on prostate cancer progression and metastasis. Front Oncol, 13: 1162644. [DOI:10.3389/fonc.2023.1162644]
9. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, et al. (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 118: 3065-3074. [DOI:10.1172/JCI34739]
10. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C, Maira S-M (2009) Specific apoptosis induction by the dual PI3K/mTOR inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA, 106: 22299-22304. [DOI:10.1073/pnas.0905152106]
11. Fokas E, Yoshimura M, Prevo R, Higgins G, Hackl W, Maira SM, Bernhard EJ, McKenna WG, Muschel RJ (2012) NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol, 7: 48. [DOI:10.1186/1748-717X-7-48]
12. Chen D, Lin X, Zhang C, Liu Z, Chen Z, Li Z, Wang J, Li B, Hu Y, Dong B, et al. (2018) Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway article. Cell Death Dis, 9: 123. [DOI:10.1038/s41419-017-0132-2]
13. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res, 68: 9221-9230. [DOI:10.1158/0008-5472.CAN-08-1740]
14. King L, Bernaitis N, Christie D, Chess-Williams R, Sellers D, McDermott C, Dare W, Anoopkumar-Dukie S (2022) Drivers of radioresistance in prostate cancer. J Clin Med, 11: 5637. [DOI:10.3390/jcm11195637]
15. Palacios DA, Miyake M, Rosser CJ (2013) Radiosensitization in prostate cancer: mechanisms and targets. BMC Urol, 13: 4. [DOI:10.1186/1471-2490-13-4]
16. Bitting RL, Armstrong AJ (2013) Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr-Relat Cancer, 20: 83-99. [DOI:10.1530/ERC-12-0394]
17. Choi EJ, Ryu YK, Kim SY, Wu HG, Kim JS, Kim IH, Kim IA (2010) Targeting epidermal growth factor receptor-associated signalling pathways in non-small cell lung cancer cells: implication in radiation response. Mol Cancer Res, 8: 1027-1036. [DOI:10.1158/1541-7786.MCR-09-0507]
18. Chou TC. 2006. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev, 58: 621-681. [DOI:10.1124/pr.58.3.10]
19. Dicken H, Hensley PJ, Kyprianou N (2019) Prostate tumour neuroendocrine differentiation via EMT: The road less travelled. Asian J Urol, 6: 82-90. [DOI:10.1016/j.ajur.2018.11.001]
20. Gourdin T and Velayati A (2023) Treatments and challenges in advanced prostate cancer. Curr Opin Oncol, 35: 200-205. [DOI:10.1097/CCO.0000000000000938]
21. Ryan CJ and Tindall DJ (2011) Androgen receptor rediscovered: The new biology and targeting the androgen receptor therapeutically. J Clin Oncol, 29: 3651-3658. [DOI:10.1200/JCO.2011.35.2005]
22. Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fléchon A, Tombal B, Supiot S, Berthold D, Ronchin P, et al. (2022) Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. The Lancet, 399: 1695-1707. [DOI:10.1016/S0140-6736(22)00367-1]
23. Serafin AM, Binder AB, Böhm L (2001) Chemosensitivity of prostate tumour cell lines under conditions of G2 block abrogation. Urol Res, 29: 221-227. [DOI:10.1007/s002400100186]
24. Serafin AM, Akudugu JM, Böhm L (2003) Studies on the influence of DNA repair on radiosensitivity in prostate cell lines. Urol Res, 31: 227-231. [DOI:10.1007/s00240-003-0299-0]
25. Estébanez-Perpiñá E, Bevan CL, McEwan IJ (2021) Eighty years of targeting androgen receptor activity in prostate cancer: the fight goes on. Cancers, 13: 509. [DOI:10.3390/cancers13030509]
26. Lonergan PE and Tindall DJ (2011). Androgen receptor signalling in prostate cancer development and progression. J Carcinog, 10: 20. [DOI:10.4103/1477-3163.83937]
27. Serafin AM, Akudugu JM, Böhm L (2002) Drug resistance in prostate cancer cell lines is influenced by androgen dependence and p53 status. Urol Res, 30: 289-294. [DOI:10.1007/s00240-002-0277-y]
28. Tilley WD, Wilson CM, Marcelli M, McPhaul MJ (1990) Androgen receptor gene expression in human prostate carcinoma cell lines. Cancer Res, 50: 5382-5386.
29. Guo C, Luttrell LM, Price DT (2000) Mitogenic signalling in androgen sensitive and insensitive prostate cancer cell lines. J Urol, 163: 1027-1032. [DOI:10.1016/S0022-5347(05)67876-7]
30. Veldscholte J, Berrevoets CA, Ris-Stalpers C, Kuiper GG, Jenster G, Trapman J, Brinkmann AO, Mulder E (1992) The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol, 41: 665-669. [DOI:10.1016/0960-0760(92)90401-4]
31. Pignon J-C, Koopmansch B, Nolens G, Delacroix L, Waltregny D, Winkler R (2009) Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines. Cancer Res, 69: 2941-2949. [DOI:10.1158/0008-5472.CAN-08-3760]
32. Hastie C, Saxton M, Akpan A, Cramer R, Masters JR, Naaby-Hansen S (2005) Combined affinity labelling and mass spectrometry analysis of differential cell surface protein expression in normal and prostate cancer cells. Oncogene, 24: 5905-5913. [DOI:10.1038/sj.onc.1208747]
33. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, Jakubikova J, Maira S-M, Garcia-Echeverria C, Schlossman R, et al. (2009) Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res, 69: 5835-5842. [DOI:10.1158/0008-5472.CAN-08-4285]
34. Gravina GL, Mancini A, Scarsella L, Colapietro A, Jitariuc A, Vitale F, Marampon F, Ricevuto E, Festuccia C (2015) Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models. Tumor Biol, 37: 341-351. [DOI:10.1007/s13277-015-3725-3]
35. Kuruma H, Matsumoto H, Shiota M, Bishop J, Lamoureux F, Thomas C, Briere D, Los G, Gleave M, Fanjul A, et al. (2013) A novel antiandrogen, compound 30, suppresses castration-resistance and MDV3100-resistant prostate cancer growth in vitro and in vivo. Mol Cancer Ther, 10: 1158-1535. [DOI:10.1158/1535-7163.MCT-12-0798]
36. Zhao J, Guercio BJ, Sahasrabudhe D (2024) Current trends in chemotherapy in the treatment of metastatic prostate cancer. Cancers, 15: 3969. [DOI:10.3390/cancers15153969]
37. Akudugu JM, Howell RW (2012) A method to predict response of cell populations to cocktails of chemotherapeutics and radiopharmaceuticals: Validation with daunomycin, doxorubicin, and the alpha particle emitter 210Po. Nucl Med Biol, 39: 954-961. [DOI:10.1016/j.nucmedbio.2012.01.011]
38. Pasternack JB, Domogauer JD, Khullar A, Akudugu JM, Howell RW (2014) The advantage of antibody cocktails for targeted alpha therapy depends on specific activity. J Nucl Med, 55: 2012-2019. [DOI:10.2967/jnumed.114.141580]
39. Hamunyela R, Serafin A, Hamid M, Maleka S, Achel D, Akudugu J (2015) A cocktail of specific inhibitors of HER-2, PI3K, and mTOR radiosensitises human breast cancer cells. J Cancer Biol Therap, 1: 46-56. [DOI:10.18314/gjct.v1i1.33]
40. Thomas C, Lamoureux F, Crafter C, Davies BR, Beraldi E, Fazli L, Kim S, Thaper D, Gleave ME, Zoubeidi A (2013) Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo. Mol Cancer Ther, 10: 1158-1535. [DOI:10.1016/j.juro.2013.02.1703]
41. Murga JD, Moorji SM, Han AQ, Magargal WW, DiPippo VA, Olson WC (2015) Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer. Prostate, 75: 242-254. [DOI:10.1002/pros.22910]
42. Park H, Kim Y, Sul J, Jeong IG, Yi H, Ahn JB, Kang JS, Yun J, Hwang JJ, Kim C-S (2015) Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration-resistant prostate cancer. Prostate, 75: 1747-1759. [DOI:10.1002/pros.23057]
43. Dirican A, Atmaca H, Bozkurt E, Erten C, Karaca B, Uslu R (2014) Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU145 human prostate cancer cells by modulating PI3K-AKT pathway. Clin Transl Oncol, 17: 145-151. [DOI:10.1007/s12094-014-1206-6]
44. Skvortsova I, Skvortsov S, Stasyk T, Raju U, Popper B-A, Schiestl B, Von Guggenberg E, Neher A, Bonn GK, Huber LA, et al. (2008) Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics, 8: 4521-4533. [DOI:10.1002/pmic.200800113]
45. Raith F, O'Donovan DH, Lemos C, Politz O, Haendler B (2023) Addressing the reciprocal crosstalk between the AR and the PI3K/AKT/mTOR signalling pathways for prostate cancer treatment. Int J Mol Sci, 24: 2289. [DOI:10.3390/ijms24032289]
46. Hamunyela R, Serafin A, Akudugu J (2016) Combined inhibition of PI3K, mTOR and Bcl-2 significantly radiosensitises progesterone and oestrogen receptor negative breast cancer cells. J Cancer Biol Therap, 1: 101-108. [DOI:10.18314/gjct.v2i1.138]
47. Hamid M, Hamunyela R, Serafin A, Akudugu J (2016) Inhibition of PI3K and mTOR sensitises oestrogen receptor positive human breast cancer cells to a large fraction of radiation dose. J Cancer Biol Therap, 1: 93-100. [DOI:10.18314/gjct.v2i1.74]
48. Hamid MB, Serafin AM, Akudugu JM (2021) Selective therapeutic benefit of X-rays and inhibitors of EGFR, PI3K/mTOR, and Bcl-2 in breast, lung, and cervical cancer cells. Eur J Pharmacol, 912: 174612. [DOI:10.1016/j.ejphar.2021.174612]
49. Speers C, Zhao SG, Chandler B, Liu M, Wilder-Romans K, Olsen E, Nyati S, Ritter C, Alluri PG, Kothari V, et al. (2017) Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer. Breast Cancer, 3: 1-10. [DOI:10.1038/s41523-017-0038-2]
50. Potiron VA, Abderrhamani R, Giang E, Chiavassa S, Di Tomaso E, Maira S-M, Paris F, Supiot S (2013) Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions. Radiother Oncol, 106: 138-146. [DOI:10.1016/j.radonc.2012.11.014]
Maleka S, Serafin A, Akudugu J. Specific inhibitors of PI3K, mTOR and AR exhibit strong synergism and radiosensitization in human prostate cell lines. Int J Radiat Res 2025; 23 (1) :211-223 URL: http://ijrr.com/article-1-6056-en.html