ENHANCED ANTICANCER POTENCY OF GEMCITABINE IN COMBINATION WITH PROPOFOL IN PROSTATE CANCER

Abstract

For this purpose, the use of anesthetic agents is considered as a new alternative. Therefore, in the present study, the effects of propofol which is an intravenous anesthetic on its own and simultaneously with gemcitabine were investigated on human prostate cancer brain metastasis DU145 and bone metastasis PC3 cells at both cellular and molecular levels. In the first stage of our study, toxic doses of these agents were determined by using the CVDK-8 and lactate dehydrogenase release test. In the following phases, TAC and TOS analyzes were performed to determine the biochemical effects of these agents on cell lines, and also western blot analysis was used to show the inhibition of important oncogenic PI3K/AKT/mTOR pathway in cells treated with these agents. Propofol was found to increase the effectiveness of gemcitabine in both cells. When propofol and gemcitabine were administered simultaneously at high concentrations, they reduced cell viability and increased LDH activity. According to the results obtained from the western blot analysis, the combination of these two agents was found to lead to synergistic inhibition of the PI3K/Akt/mTOR pathway.

Keywords

• cytotoxicity
• gemcitabine
• propofol
• prostate cancer

References

1. 1. K. Hariharan, V. Padmanabha, Demography and disease characteristics of prostate cancer in India, Indian J. Urol., 32 (2016) 103-108.
2. 2. C.H. Pernar, E.M. Ebot, K.M. Wilson, L.A. Mucci, The epidemiology of prostate cancer, Cold Spring Harb. Perspect. Med., 8 (2018) a030361.
3. 3. M.C. Markowski, M.A. Carducci, Early use of chemotherapy in metastatic prostate cancer, Cancer Treat, Rev., 55 (2017) 218-224.
4. 4. H.J. Lavery, M.R. Cooperberg, Clinically localized prostate cancer in 2017: A review of comparative effectiveness, Urol. Oncol., 35 (2017) 40-41.
5. 5. J. Song, Y. Song, W. Guo, J. Jia, Y. Jin, A. Bai, Regulatory roles of KDR antisense oligonucleotide on the proliferation of human prostate cancer cell line PC-3, J. BUON., 19 (2014) 770-774.
6. 6. T. Jurić, J.S. Katanić Stanković, G. Rosić, D. Selaković, J. Joksimović, D. Mišić, V. Stanković, V. Mihailović, Protective effects of Alchemilla vulgaris L. extracts against cisplatin-induced toxicological alterations in rats, South African Journal of Botany, 128 (2020) 141-151.
7. 7. Q.H. Du, Y.B. Xu, M.Y. Zhang, P. Yun, C.Y. He, Propofol induces apoptosis and increases gemcitabine sensitivity in pancreatic cancer cells in vitro by inhibition of nuclear factor-κB activity, World J. Gastroenterol., 19 (2013) 5485-5492.
8. 8. V. Fodale, M.G. D’Arrigo, S. Triolo, S. Mondello, D. La Torre, Anesthetic techniques and cancer recurrence after surgery", The Scientific World Journal, 5 (2014) 328513.

9. 9. W. Yang, J. Cai, C. Zabkiewicz, H. Zhang, F. Ruge, W.G. Jiang, The effects of anesthetics on recurrence and metastasis of cancer, and clinical implications, World J. Oncol., 8 (2017) 63-70.
10. 10. J. Song, Y. Shen, J. Zhang, Q. Lian, Mini profile of potential anticancer properties of propofol. PLoS One, 9 (2014) e114440.
11. 11. T. Mammoto, M. Mukai, A. Mammoto, Y. Yamanaka, Y. Hayashi, T. Mashimo, Y. Kishi, H. Nakamura, Intravenous anesthetic, propofol inhibits invasion of cancer cells, Cancer Lett., 18 (2002) 165-170.
12. 12. R. Melamed, S. Bar-Yosef, G. Shakhar, S. Ben-Eliyahu, Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures, Anesth. Analg. 97 (2003) 1331-1339.
13. 13. R.A. Siddiqui, M. Zerouga, M. Wu, A. Castillo, K. Harvey, G.P Zaloga, W. Stillwell, Anticancer properties of propofoldocosahexaenoate and propofol-eicosapentaenoate on breast cancer cells, Breast Cancer Res.,7 (2005) 645-654.
14. 14. J. Homburger, S. Meiler, Anesthesia drugs, immunity, and long-term outcome, Curr. Opin. Anaesthesiol. 19 (2006) 423-428.
15. 15. H. Wada, S. Seki, T. Takahashi, N. Kawarabayashi, H. Higuchi, Y. Habu, S. Sugahara, T. Kazama, Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance, Anesthesiology, 106 (2007) 499-506.
16. 16. X.F. Ren, W.Z. Li, F.Y. Meng, C.F. Lin, Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients, Anesthesia, 65 (2010) 478-482.
17. 17. H. Huang, L. Benzonana, H. Zhao, H. Watts, N. Perry, C. Bevan, R. Brown, D. Ma, Prostate cancer cell malignancy via modulation of HIF-1a pathway with isoflurane and propofol alone and in combination, Br. J. Cancer, 111 (2014) 1338-1349.
18. 18. Y. Sun, H. Sun, Propofol exerts anticancer activity on hepatocellular carcinoma cells by raising lncRNA DGCR5, J. Cell Physiol., 235 (2020) 2963-2972.
19. 19. F.C. Kang, S.C. Wang, E.C. So, M.M. Chang, K.L. Wong, K.S. Cheng, Y.C. Chen, B.M. Huang, Propofol may increase caspase and MAPK pathways, and suppress the Akt pathway to induce apoptosis in MA‑10 mouse Leydig tumor cells, Oncol. Rep., 41 (2019) 3565-3574.
20. 20. D. Wang, T. Yang, J. Liu, Y. Liu, N. Xing, J. He, J .Yang, Y. Ai, Propofol inhibits the migration and invasion of glioma cells by blocking the PI3K/AKT pathway through miR-206/ROCK1 axis, Onco. Targets Ther., 13 (2020) 361-370.
21. 21. Z. Zhang, M. Zang, S. Wang, C. Wang, Effects of propofol on human cholangiocarcinoma and the associated mechanisms. Exp. Ther. Med., 17 (2019) 472-478. 22. V. Cucchiara, M.R. Cooperberg, M. Dall'Era, D.W. Lin, F. Montorsi, J.A. Schalken, C.P. Evans, Genomic markers in prostate cancer decision making, Eur. Urol., 73 (2018) 572-582.
22. 23. F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68 (2018) 394-424.
23. 24. Z.J. Ren, D.H. Cao, Q. Zhang, P.W. Ren, L.R. Liu, Q. Wei, W.R. Wei, Q. Dong, First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis, BMC Cancer., 19 (2019) 871.
24. 25. M.F. Leitzmann, S. Rohrmann, Risk factors for the onset of prostatic cancer: age, location, and behavioral correlates, Clin. Epidemiol., 4 (2012) 1-11.
25. 26. A. Heidenreich, P.J. Bastian, J. Bellmunt, M. Bolla, S. Joniau, T. van der Kwast, M. Mason, V. Matveev, T. Wiegel, F. Zattoni, N. Mottet, U. European Association of. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013 Eur. Urol., 65 (2014) 124-137.
26. 27. J. Cuzick, M.A. Thorat, G. Andriole, O.W. Brawley, P.H. Brown, Z. Culig, R.A. Eeles, L.G. Ford, F.C. Hamdy, L. Holmberg, D. Ilic, T.J. Key, C. La Vecchia, H. Lilja, M. Marberger, F.L. Meyskens, L.M. Minasian, C. Parker, H.L. Parnes, S. Perner, H. Rittenhouse, J. Schalken, H.P. Schmid, B.J. Schmitz-Dräger, F.H. Schröder, A. Stenzl, B. Tombal, T.J. Wilt, A. Wolk, Prevention and early detection of prostate cancer. Lancet. Oncol., 15 (2014) e484-492.
27. 28. A. Pettersson, D. Robinson, H. Garmo, L. Holmberg, P. Stattin, Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study, Ann. Oncol., 29 (2018) 377-385.
28. 29. C. Wei, Y. Pan, H. Huang, Y.P. Li, Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels, Eur. Rev. Med. Pharmacol. Sci., 22 (2018) 40-45.
29. 30. A. Shakeri-Zadeh, S. Khoei, S. Khoee, A.M. Sharifi, M.B. Shiran, Targeted, monitored, and controlled chemotherapy: a multimodal nanotechnology-based approach against cancer, ISRN Nanotechnology, 2013 (2013).
30. 31. P.E. Marik, Propofol: therapeutic indications and side-effects, Curr. Pharm. Des., 10 (2004) 3639-3649.
31. 32. W. Xu, J. Zheng, S. Bie, L. Kang, Q. Mao, W. Liu, J. Guo, J. Lu, R. Xia, Propofol inhibits Wnt signaling and exerts anticancer activity in glioma cells, Oncol. Lett., 16 (2018) 402-408.
32. 33. X.G. Guo, S. Wang, Y.B. Xu, J. Zhuang, Propofol suppresses invasion, angiogenesis and survival of EC-1 cells in vitro by regulation of S100A4 expression, Eur. Rev. Med. Pharmacol. Sci., 19 (2015) 4858-4865.
33. 34. Q. Li, L. Zhang, Y. Han, Z. Jiang, Q. Wang, Propofol reduces MMPs expression by inhibiting NF-κB activity in human MDA-MB-231 cells, Biomed. Pharmacother., 66 (2012) 52-56.
34. 35. X. Xu, G. Wu, Y. Liu, L. Zhang, Effects of propofol on hippocampal neuron viability, Childs Nerv. Syst., 36 (2020) 1995-2002.
35. 36. Z. Shang, H. Feng, L. Cui, W. Wang, H. Fu, Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells, Oncol. Lett., 15 (2018) 630-634.
36. 37. S.G. Xing, K.J. Zhang, J.H. Qu, Y.D. Ren, Q. Luan, Propofol induces apoptosis of non-small cell lung cancer cells via ERK1/2-dependent upregulation of PUMA, Eur. Rev. Med. Pharmacol. Sci., 22 (2018) 4341-4349.
37. 38. S.S. Hsu, C.R. Jan, W.Z. Liang, Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes, Environ. Toxicol., 32 (2017) 2440-2454.
38. 39. S. Reuter, S.C. Gupta, M.M. Chaturvedi, B.B. Aggarwal, Oxidative stress, inflammation, and cancer: how are they linked?, Free Radic. Biol. Med., 49 (2010) 1603-1616.
39. 40. X.G. Lei, J.H. Zhu, W.H. Cheng, Y. Bao, Y.S. Ho, A.R. Reddi, A. Holmgren, E.S. Arnér, Paradoxical roles of antioxidant enzymes: basic mechanisms and health implications, Physiol, Rev., 96 (2016) 307-364.
40. 41. V. Rojas, K.M. Hirshfield, S. Ganesan, L. Rodriguez-Rodriguez, Molecular characterization of epithelial ovarian cancer: implications for diagnosis and treatment, Int. J. Mol. Sci., 17 (2016) 2113.
41. 42. J. Wang, J. Yi, Cancer cell killing via ROS: to increase or decrease that is the question, Cancer Biol. Ther., 7 (2008), 1875-1884.
42. 43. A. Le, C.R. Cooper, A.M. Gouw, R. Dinavahi, A. Maitra, L.M. Deck, R.E. Royer, D.L. Vander Jagt, G.L. Semenza, C.V. Dang, Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression, Proc. Natl. Acad. Sci. USA., 107 (2010) 2037-2042.
43. 44. Z. Liu, J. Zhang, G. Hong, J. Quan, L. Zhang, M. Yu, Propofol inhibits growth and invasion of pancreatic cancer cells through regulation of the miR-21/Slug signaling pathway, Am. J. Transl. Res., 8 (2016) 4120-4133.
44. 45. B. Liang, T. Dong, Effects of propofol on invasion and migration of colon cancer cells and JAK2/STAT3 signaling pathway, Zhong Nan Da Xue Xue Bao Yi Xue Ban., 45 (2020;) 290-296.
45. 46. B.S. Carver, C. Chapinski, J. Wongvipat, H. Hieronymus, Y. Chen, S. Chandarlapaty, V.K. Arora, C. Le, J. Koutcher, H. Scher, P.T. Scardino, N. Rosen, C.L. Sawyers, Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer, Cancer Cell., 19 (2011) 575-586.
46. 47. M. Crumbaker, L. Khoja, A.M. Joshua, AR Signaling and the PI3K pathway in prostate cancer, Cancers., 9 (2017) 34.
47. 48. H. Pearson, J. Li, V. Méniel, C. Fennell, P. Waring, K.G. Montgomery, R.J. Rebello, A.A. MacPherson, S. Koushyar, L. Furic, C. Cullinane, R.W. Clarkson, M.J. Smalley, K.J. Simpson, T.J. Phesse, P.R. Shepherd, P.O. Humbert, O.J. Sansom, W.A. Phillips, Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth, Cancer Discov., 8 (2018) 764-779.
48. 49. R.L. Bitting, A.J. Armstrong, Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer, Endocr. Relat. Cancer., 20 (2013) R83-R99.
49. 50. A.C. Hsieh, M.P. Edlind, PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance, Asian J. Androl., 16 (2014) 378-386.
50. 51. P. Toren, A. Zoubeidi, Targeting the PI3K/Akt pathway in prostate cancer: Challenges and opportunities (Review), Int. J. Oncol., 45 (2014) 1793-1801.
51. 52. J. Yang, J. Nie, X. Ma, Y. Wei, Y. Peng, X. Wei, Targeting PI3K in cancer: Mechanisms and advances in clinical trials, Mol. Cancer., 18 (2019) 26.
52. 53. Z. Wang, G. Luo, Z. Qiu, Akt inhibitor MK-2206 reduces pancreatic cancer cell viability and increases the efficacy of gemcitabine, Oncol. Lett., 19 (2020) 1999-2004.