Anticancer potential of novel curcumin analogs towards castrate-resistant prostate cancer

Chen,Shuli; Nimick,Mhairi; Cridge,Andrew G.; Hawkins,Bill C.; Rosengren,Rhonda J.

doi:10.3892/ijo.2017.4207

Anticancer potential of novel curcumin analogs towards castrate-resistant prostate cancer

Authors:
- Shuli Chen
- Mhairi Nimick
- Andrew G. Cridge
- Bill C. Hawkins
- Rhonda J. Rosengren
View Affiliations

Affiliations: Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New Zealand, Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand, Department of Chemistry, University of Otago, Dunedin 9016, New Zealand
Published online on: November 20, 2017 https://doi.org/10.3892/ijo.2017.4207
Pages: 579-588

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Prostate cancer is initially sensitive to hormone therapy; however, over time the majority of patients progress to a hormone-insensitive form classified as castration-resistant prostate cancer (CRPC). CRPC is highly metastatic and patients have a poor prognosis. Thus, new drugs for the treatment of this disease are required. In this study, we therefore examined the cytotoxic effects and anticancer mechanism(s) of action of second generation curcumin analogs towards CRPC cells. For this purpose, PC3 and DU145 cells were treated with a series of curcumin analogs at 0-10 µM for 72 h and cytotoxicity was determined by the sulforhodamine B (SRB) assay. Two compounds, 1-isopropyl-3,5-bis(pyridin-3-ylmethylene)-4-piperidone (RL118) and 1-methyl-3,5-[(6-methoxynaphthalen-2-yl)methylene]-4-piperidone (RL121), were found to have the most potent cytotoxic effect with EC50 values of 0.50 and 0.58 µM in the PC3 cells and EC50 values of 0.76 and 0.69 µM in the DU145 cells, respectively. Thus, further experiments were performed focusing on these two compounds. Flow cytometry was performed to determine their effects on the cell cycle and apoptosis. Both analogs increased the number of cells in the G2/M phase of the cell cycle and induced apoptosis. Specifically, in the PC3 cells, RL121 increased the number of cells in the G2/M phase by 86% compared to the control, while RL118 increased the number of cells in the G2/M phase by 42% compared to the control after 24 h. Moreover, both RL118 and RL121 induced the apoptosis of both cell lines. In the DU145 cells, a 38-fold increase in the number of apoptotic cells was elicited by RL118 and a 78-fold increase by RL121 compared to the control. Furthermore, the effects of both analogs on the expression of key proteins involved in cell proliferation were also determined by western blot analysis. The results revealed that both analogs inhibited the expression of nuclear factor (NF)-κB (p65/RelA), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), p-4E-BP1, mammalian target of rapamycin (mTOR), p-mTOR, AKT and p-AKT. Thus, the findings of this study provide evidence that RL118 and RL121 have potent anticancer activity against CPRC cells, and both analogs warrant further investigation in vivo.

View Figures

View References

1	Greenlee RT, Murray T, Bolden S and Wingo PA: Cancer statistics, 2000. CA Cancer J Clin. 50:7–33. 2000. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI
3	Karantanos T, Corn PG and Thompson TC: Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 32:5501–5511. 2013. View Article : Google Scholar : PubMed/NCBI
4	Marques RB, Dits NF, Erkens-Schulze S, van Weerden WM and Jenster G: Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models. PLoS One. 5:e135002010. View Article : Google Scholar : PubMed/NCBI
5	Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P and Goel A: Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-κB and Src protein kinase signaling pathways. PLoS One. 8:e572182013. View Article : Google Scholar
6	Sadzuka Y, Nagamine M, Toyooka T, Ibuki Y and Sonobe T: Beneficial effects of curcumin on antitumor activity and adverse reactions of doxorubicin. Int J Pharm. 432:42–49. 2012. View Article : Google Scholar : PubMed/NCBI
7	Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY and Cheng AL: Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis. 21:331–335. 2000. View Article : Google Scholar : PubMed/NCBI
8	Strimpakos AS and Sharma RA: Curcumin: Preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 10:511–545. 2008. View Article : Google Scholar : PubMed/NCBI
9	Khor TO, Keum YS, Lin W, Kim JH, Hu R, Shen G, Xu C, Gopalakrishnan A, Reddy B, Zheng X, et al: Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res. 66:613–621. 2006. View Article : Google Scholar : PubMed/NCBI
10	Dorai T, Gehani N and Katz A: Therapeutic potential of curcumin in human prostate cancer-I. curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. Prostate Cancer Prostatic Dis. 3:84–93. 2000. View Article : Google Scholar
11	Anand P, Kunnumakkara AB, Newman RA and Aggarwal BB: Bioavailability of curcumin: Problems and promises. Mol Pharm. 4:807–818. 2007. View Article : Google Scholar : PubMed/NCBI
12	Adams BK, Cai J, Armstrong J, Herold M, Lu YJ, Sun A, Snyder JP, Liotta DC, Jones DP and Shoji M: EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. Anticancer Drugs. 16:263–275. 2005. View Article : Google Scholar : PubMed/NCBI
13	Wei X, Zhou D, Wang H, Ding N, Cui XX, Wang H, Verano M, Zhang K, Conney AH, Zheng X, et al: Effects of pyridine analogs of curcumin on growth, apoptosis and NF-κB activity in prostate cancer PC-3 cells. Anticancer Res. 33:1343–1350. 2013.PubMed/NCBI
14	Yadav B, Taurin S, Rosengren RJ, Schumacher M, Diederich M, Somers-Edgar TJ and Larsen L: Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin. Bioorg Med Chem. 18:6701–6707. 2010. View Article : Google Scholar : PubMed/NCBI
15	Yadav B, Taurin S, Larsen L and Rosengren RJ: RL66 a second-generation curcumin analog has potent in vivo and in vitro anticancer activity in ER-negative breast cancer models. Int J Oncol. 41:1723–1732. 2012. View Article : Google Scholar : PubMed/NCBI
16	Yadav B, Taurin S, Larsen L and Rosengren RJ: RL71, a second-generation curcumin analog, induces apoptosis and downregulates Akt in ER-negative breast cancer cells. Int J Oncol. 41:1119–1127. 2012. View Article : Google Scholar : PubMed/NCBI
17	Somers-Edgar TJ, Taurin S, Larsen L, Chandramouli A, Nelson MA and Rosengren RJ: Mechanisms for the activity of heterocyclic cyclohexanone curcumin derivatives in estrogen receptor negative human breast cancer cell lines. Invest New Drugs. 29:87–97. 2011. View Article : Google Scholar
18	Stuart EC, Jarvis RM and Rosengren RJ: In vitro mechanism of action for the cytotoxicity elicited by the combination of epigallocatechin gallate and raloxifene in MDA-MB-231 cells. Oncol Rep. 24:779–785. 2010.PubMed/NCBI
19	Beresford SA, Davies MA, Gallick GE and Donato NJ: Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PCc-3 prostate cancer cells. J Interferon Cytokine Res. 21:313–322. 2001. View Article : Google Scholar : PubMed/NCBI
20	Samaan N, Zhong Q, Fernandez J, Chen G, Hussain AM, Zheng S, Wang G and Chen QH: Design, synthesis, and evaluation of novel heteroaromatic analogs of curcumin as anti-cancer agents. Eur J Med Chem. 75:123–131. 2014. View Article : Google Scholar : PubMed/NCBI
21	Mazumder A, Gould M, Taurin S, Nicholson H and Rosengren R: Raloxifene potentiates the cytotoxicity induced by RL91, a second generation curcumin analog, in PC3 prostate cancer cells. Toxicologist. 132:1462013.
22	Zhang X, Chen M, Zou P, Kanchana K, Weng Q, Chen W, Zhong P, Ji J, Zhou H, He L, et al: Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells. BMC Cancer. 15:8662015. View Article : Google Scholar : PubMed/NCBI
23	Lin L, Hutzen B, Ball S, Foust E, Sobo M, Deangelis S, Pandit B, Friedman L, Li C, Li PK, et al: New curcumin analogues exhibit enhanced growth-suppressive activity and inhibit AKT and signal transducer and activator of transcription 3 phosphorylation in breast and prostate cancer cells. Cancer Sci. 100:1719–1727. 2009. View Article : Google Scholar : PubMed/NCBI
24	Chiu TL and Su CC: Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med. 23:469–475. 2009.PubMed/NCBI
25	Wong RS: Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 30:872011. View Article : Google Scholar : PubMed/NCBI
26	Khan N, Adhami VM and Mukhtar H: Apoptosis by dietary agents for prevention and treatment of prostate cancer. Endocr Relat Cancer. 17:R39–R52. 2010. View Article : Google Scholar
27	Mandalapu D, Saini KS, Gupta S, Sharma V, Yaseen Malik M, Chaturvedi S, Bala V, Hamidullah, Thakur S, Maikhuri JP, et al: Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines. Bioorg Med Chem Lett. 26:4223–4232. 2016. View Article : Google Scholar : PubMed/NCBI
28	Wei X, Du ZY, Cui XX, Verano M, Mo RQ, Tang ZK, Conney AH, Zheng X and Zhang K: Effects of cyclohexanone analogues of curcumin on growth, apoptosis and NF-κB activity in PC-3 human prostate cancer cells. Oncol Lett. 4:279–284. 2012.PubMed/NCBI
29	Oliver KM, Taylor CT and Cummins EP: Hypoxia. Regulation of NFkappaB signalling during inflammation: The role of hydroxylases. Arthritis Res Ther. 11:2152009. View Article : Google Scholar : PubMed/NCBI
30	Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, et al: Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-kappaB activity. J Exp Med. 201:105–115. 2005. View Article : Google Scholar : PubMed/NCBI
31	Maxwell PJ, Gallagher R, Seaton A, Wilson C, Scullin P, Pettigrew J, Stratford IJ, Williams KJ, Johnston PG and Waugh DJ: HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene. 26:7333–7345. 2007. View Article : Google Scholar : PubMed/NCBI
32	Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gélinas C and Rabson AB: Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate. 52:183–200. 2002. View Article : Google Scholar : PubMed/NCBI
33	Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, et al: Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 172:1717–1728. 2008. View Article : Google Scholar : PubMed/NCBI
34	Lindholm PF, Bub J, Kaul S, Shidham VB and Kajdacsy-Balla A: The role of constitutive NF-kappaB activity in PC-3 human prostate cancer cell invasive behavior. Clin Exp Metastasis. 18:471–479. 2000. View Article : Google Scholar
35	Lessard L, Bégin LR, Gleave ME, Mes-Masson AM and Saad F: Nuclear localisation of nuclear factor-kappaB transcription factors in prostate cancer: An immunohistochemical study. Br J Cancer. 93:1019–1023. 2005. View Article : Google Scholar : PubMed/NCBI
36	Domingo-Domenech J, Oliva C, Rovira A, Codony-Servat J, Bosch M, Filella X, Montagut C, Tapia M, Campás C, Dang L, et al: Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity. Clin Cancer Res. 12:5578–5586. 2006. View Article : Google Scholar : PubMed/NCBI
37	Ross JS, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP Jr, Kaur P, Gray K and Stringer B: Expression of nuclear factor-κ B and IκBα proteins in prostatic adenocarcinomas: Correlation of nuclear factor-κB immunoreactivity with disease recurrence. Clin Cancer Res. 10:2466–2472. 2004. View Article : Google Scholar : PubMed/NCBI
38	Chakraborty M, Qiu SG, Vasudevan KM and Rangnekar VM: Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. Cancer Res. 61:7255–7263. 2001.PubMed/NCBI
39	Jin R, Sterling JA, Edwards JR, DeGraff DJ, Lee C, Park SI and Matusik RJ: Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS One. 8:e609832013. View Article : Google Scholar : PubMed/NCBI
40	Huang S, Pettaway CA, Uehara H, Bucana CD and Fidler IJ: Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 20:4188–4197. 2001. View Article : Google Scholar : PubMed/NCBI
41	Yang CH, Yue J, Sims M and Pfeffer LM: The curcumin analog EF24 targets NF-κB and miRNA-21, and has potent anticancer activity in vitro and in vivo. PLoS One. 8:e711302013. View Article : Google Scholar
42	Olivera A, Moore TW, Hu F, Brown AP, Sun A, Liotta DC, Snyder JP, Yoon Y, Shim H, Marcus AI, et al: Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): Anti-inflammatory and anti-cancer properties. Int Immunopharmacol. 12:368–377. 2012. View Article : Google Scholar
43	Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW and Burgess AW: Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp Cell Res. 284:31–53. 2003. View Article : Google Scholar : PubMed/NCBI
44	Nicholson RI, Gee JM and Harper ME: EGFR and cancer prognosis. Eur J Cancer. 37(Suppl 4): S9–S15. 2001. View Article : Google Scholar : PubMed/NCBI
45	Di Lorenzo G, Tortora G, D'Armiento FP, De Rosa G, Staibano S, Autorino R, D'Armiento M, De Laurentiis M, De Placido S, Catalano G, et al: Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 8:3438–3444. 2002.PubMed/NCBI
46	Kim JH, Xu C, Keum YS, Reddy B, Conney A and Kong AN: Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with β-phenylethyl isothiocyanate and curcumin. Carcinogenesis. 27:475–482. 2006. View Article : Google Scholar
47	Shinde SR and Maddika S: PTEN modulates EGFR late endocytic trafficking and degradation by dephosphorylating Rab7. Nat Commun. 7:106892016. View Article : Google Scholar : PubMed/NCBI
48	Rush JS, Quinalty LM, Engelman L, Sherry DM and Ceresa BP: Endosomal accumulation of the activated epidermal growth factor receptor (EGFR) induces apoptosis. J Biol Chem. 287:712–722. 2012. View Article : Google Scholar :
49	Dillon RL, White DE and Muller WJ: The phosphatidyl inositol 3-kinase signaling network: Implications for human breast cancer. Oncogene. 26:1338–1345. 2007. View Article : Google Scholar : PubMed/NCBI
50	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
51	Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, et al: Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 275:24500–24505. 2000. View Article : Google Scholar : PubMed/NCBI
52	Shimizu Y, Segawa T, Inoue T, Shiraishi T, Yoshida T, Toda Y, Yamada T, Kinukawa N, Terada N, Kobayashi T, et al: Increased Akt and phosphorylated Akt expression are associated with malignant biological features of prostate cancer in Japanese men. BJU Int. 100:685–690. 2007. View Article : Google Scholar : PubMed/NCBI
53	Morgan TM, Koreckij TD and Corey E: Targeted therapy for advanced prostate cancer: Inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 9:237–249. 2009. View Article : Google Scholar : PubMed/NCBI
54	Ayala G, Thompson T, Yang G, Frolov A, Li R, Scardino P, Ohori M, Wheeler T and Harper W: High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence. Clin Cancer Res. 10:6572–6578. 2004. View Article : Google Scholar : PubMed/NCBI
55	Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S and Ghosh PM: Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 64:5232–5236. 2004. View Article : Google Scholar : PubMed/NCBI
56	Mimeault M, Johansson SL and Batra SK: Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies. PLoS One. 7:e319192012. View Article : Google Scholar
57	Song MS, Salmena L and Pandolfi PP: The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 13:283–296. 2012.PubMed/NCBI
58	Pópulo H, Lopes JM and Soares P: The mTOR signalling pathway in human cancer. Int J Mol Sci. 13:1886–1918. 2012. View Article : Google Scholar : PubMed/NCBI
59	Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, Vanpatten K, Highstrom L, Pestano GA and Nagle RB: Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate. 66:1203–1212. 2006. View Article : Google Scholar : PubMed/NCBI
60	Liu G, Zhang Y, Bode AM, Ma WY and Dong Z: Phosphorylation of 4E-BP1 is mediated by the p38/MSK1 pathway in response to UVB irradiation. J Biol Chem. 277:8810–8816. 2002. View Article : Google Scholar : PubMed/NCBI
61	Haystead TA, Haystead CM, Hu C, Lin TA and Lawrence JC Jr: Phosphorylation of PHAS-I by mitogen-activated protein (MAP) kinase. Identification of a site phosphorylated by MAP kinase in vitro and in response to insulin in rat adipocytes. J Biol Chem. 269:23185–23191. 1994.PubMed/NCBI