Inhibitory activity of apogossypol in human prostate cancer in vitro and in vivo Corrigendum in /10.3892/mmr.2018.8571

Zhan,Wenhua; Hu,Xingbin; Yi,Jing; An,Qunxing; Huang,Xiaofeng

doi:10.3892/mmr.2015.3326

Inhibitory activity of apogossypol in human prostate cancer in vitro and in vivo

Corrigendum in: /10.3892/mmr.2018.8571

Authors:
- Wenhua Zhan
- Xingbin Hu
- Jing Yi
- Qunxing An
- Xiaofeng Huang
View Affiliations

Affiliations: Department of Radiotherapy, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Central Laboratory, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: February 10, 2015 https://doi.org/10.3892/mmr.2015.3326
Pages: 4142-4148
Copyright: © Zhan et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Apogossypol, a gossypol derivative, is a novel small‑molecule inhibitor of the Bcl‑2 family proteins and has been demonstrated to have anti‑tumor activities. Prostate cancer is the most common malignancy in males, for which chemotherapy is the usual treatment option in clinical practice. The aim of the present study was to investigate the growth inhibitory effects of apogossypol on prostate cancers in vitro and in vivo. An MTT assay and a colony formation assay were used to assess the anti‑survival and anti‑proliferation effects of apogossypol in LNCaP cells. Immunofluorescence was performed in order to detect the expression levels of apoptosis‑associated proteins in xenograft tumors following apogossypol treatment. Apogossypol exerted strong anti‑tumor effects on LNCaP cells in a dose‑dependent manner. Furthermore, immunofluorescence revealed that apogossypol inhibited the growth and proliferation of prostate cancer cells by downregulating Bcl‑2 protein expression and activating caspase‑3 and ‑8. In addition, the in vivo study indicated that apogossypol significantly inhibited tumor growth in a dose‑dependent manner with reduced toxicity compared with gossypol. In conclusion, the present study indicated that apogossypol effectively inhibited the growth and proliferation of prostate cancer cells and may be a potential agent for prostate cancer therapy.

View Figures

View References

1	Parkin DM: International variation. Oncogene. 23:6329–6340. 2004. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
3	Morse MA and Stoner GD: Cancer chemoprevention: principles and prospects. Carcinogenesis. 14:1737–1746. 1993. View Article : Google Scholar : PubMed/NCBI
4	Debatin KM: Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother. 53:153–159. 2004. View Article : Google Scholar : PubMed/NCBI
5	Oltersdorf T, Elmore SW, Shoemaker AR, et al: An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature. 435:677–681. 2005. View Article : Google Scholar : PubMed/NCBI
6	Krajewska M, Fenoglio-Preiser CM, Krajewski S, et al: Immunohistochemical analysis of Bcl-2 family proteins in adenocarcinomas of the stomach. Am J Pathol. 149:1449–1457. 1996.PubMed/NCBI
7	Reed JC, Zha H, Aime-Sempe C, Takayama S and Wang HG: Structure-function analysis of Bcl-2 family proteins: Regulators of programmed cell death. Adv Exp Med Biol. 406:99–112. 1996. View Article : Google Scholar
8	Petros AM, Olejniczak ET and Fesik SW: Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta. 1644:83–94. 2004. View Article : Google Scholar : PubMed/NCBI
9	Marzo I and Naval J: Bcl-2 family members as molecular targets in cancer therapy. Biochem Pharmacol. 76:939–946. 2008. View Article : Google Scholar : PubMed/NCBI
10	Huang Z: Small molecule inhibitors of Bcl-2 function: modulators of apoptosis and promising anticancer agents. Curr Opin Drug Discov Devel. 3:565–574. 2000.PubMed/NCBI
11	Wang S, Yang D and Lippman ME: Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule antagonists. Semin Oncol. 30(5 Suppl 16): 133–142. 2003. View Article : Google Scholar : PubMed/NCBI
12	Al-Katib AM, Sun Y, Goustin AS, et al: SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status. J Hematol Oncol. 2:82009. View Article : Google Scholar : PubMed/NCBI
13	Azmi AS and Mohammad RM: Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol. 218:13–21. 2009. View Article : Google Scholar :
14	Wei MC, Zong WX, Cheng EH, et al: Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 292:727–730. 2001. View Article : Google Scholar : PubMed/NCBI
15	Coutinho EM: Gossypol: a contraceptive for men. Contraception. 65:259–263. 2002. View Article : Google Scholar : PubMed/NCBI
16	Naik H, Petrylak D, Yagoda A, et al: Preclinical studies of gossypol in prostate carcinoma. Int J Oncol. 6:209–213. 1995.PubMed/NCBI
17	Gilbert NE, O’Reilly JE, Chang CJ, Lin YC and Brueggemeier RW: Antiproliferative activity of gossypol and gossypolone on human breast cancer cells. Life Sci. 57:61–67. 1995. View Article : Google Scholar : PubMed/NCBI
18	Bushunow P, Reidenberg MM, Wasenko J, et al: Gossypol treatment of recurrent adult malignant gliomas. J Neurooncol. 43:79–86. 1999. View Article : Google Scholar : PubMed/NCBI
19	Balakrishnan K, Wierda WG, Keating MJ and Gandhi V: Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 112:1971–1980. 2008. View Article : Google Scholar : PubMed/NCBI
20	Gunassekaran GR, Priya DK, Gayathri R and Sakthisekaran D: In vitro and in vivo studies on antitumor effects of gossypol on human stomach adenocarcinoma (AGS) cell line and MNNG induced experimental gastric cancer. Biochem Biophys Res Commun. 411:661–666. 2011. View Article : Google Scholar : PubMed/NCBI
21	Jiang J, Slivova V, Jedinak A and Sliva D: Gossypol inhibits growth, invasiveness, and angiogenesis in human prostate cancer cells by modulating NF-κB/AP-1 dependent- and independent-signaling. Clin Exp Metastasis. 29:165–178. 2012. View Article : Google Scholar
22	Baggstrom MQ, Qi Y, Koczywas M, et al: A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol. 6:1757–1760. 2011. View Article : Google Scholar : PubMed/NCBI
23	Wei J, Kitada S, Stebbins JL, et al: Synthesis and biological evaluation of Apogossypolone derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 53:8000–8011. 2010. View Article : Google Scholar : PubMed/NCBI
24	Zhang XQ, Huang XF, Hu XB, et al: Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro. Asian J Androl. 12:697–708. 2010. View Article : Google Scholar : PubMed/NCBI
25	Zhan Y, Jia G, Wu D, Xu Y and Xu L: Design and synthesis of a gossypol derivative with improved antitumor activities. Arch Pharm (Weinheim). 342:223–229. 2009. View Article : Google Scholar
26	Wei J, Rega MF, Kitada S, et al: Synthesis and evaluation of Apogossypol atropisomers as potential Bcl-xL antagonists. Cancer Lett. 273:107–113. 2009. View Article : Google Scholar :
27	Jiang J, Sugimoto Y, Liu S, et al: The inhibitory effects of gossypol on human prostate cancer cells-PC3 are associated with transforming growth factor beta1 (TGFbeta1) signal transduction pathway. Anticancer Res. 24:91–100. 2004.PubMed/NCBI
28	Karaca B, Kucukzeybek Y, Gorumlu G, et al: Profiling of angiogenic cytokines produced by hormone- and drug-refractory prostate cancer cell lines, PC-3 and DU-145 before and after treatment with gossypol. Eur Cytokine Netw. 19:176–184. 2008.PubMed/NCBI
29	Zhang M, Liu H, Tian Z, et al: Gossypol induces apoptosis in human PC-3 prostate cancer cells by modulating caspase-dependent and caspase-independent cell death pathways. Life Sci. 80:767–774. 2007. View Article : Google Scholar
30	Reed JC: Apoptosis-based therapies. Nat Rev Drug Discov. 1:111–121. 2002. View Article : Google Scholar : PubMed/NCBI
31	Adams JM and Cory S: The Bcl-2 protein family: arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
32	Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI
33	Wang JL, Liu D, Zhang ZJ, et al: Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA. 97:7124–7129. 2000. View Article : Google Scholar : PubMed/NCBI
34	Degterev A, Lugovskoy A, Cardone M, et al: Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol. 3:173–182. 2001. View Article : Google Scholar : PubMed/NCBI
35	Reed JC: Bcl-2 family proteins. Oncogene. 17:3225–3236. 1998. View Article : Google Scholar
36	Reed JC: Bcl-2 family proteins: strategies for overcoming chemoresistance in cancer. Adv Pharmacol. 41:501–532. 1997. View Article : Google Scholar : PubMed/NCBI
37	Kitada S, Leone M, Sareth S, et al: Discovery, characterization, and structure-activity relationships studies of proapoptotic poly-phenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem. 46:4259–4264. 2003. View Article : Google Scholar : PubMed/NCBI
38	Zhang M, Liu H, Guo R, et al: Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Biochem Pharmacol. 66:93–103. 2003. View Article : Google Scholar : PubMed/NCBI
39	Wang G, Nikolovska-Coleska Z, Yang CY, et al: Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem. 49:6139–6142. 2006. View Article : Google Scholar : PubMed/NCBI
40	Scopa CD, Vagianos C, Kardamakis D, Kourelis TG, Kalofonos HP and Tsamandas AC: bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with rectal cancer. Appl Immunohistochem Mol Morphol. 9:329–334. 2001. View Article : Google Scholar
41	Shelley MD, Hartley L, Groundwater PW and Fish RG: Structure-activity studies on gossypol in tumor cell lines. Anticancer Drugs. 11:209–216. 2000. View Article : Google Scholar : PubMed/NCBI
42	Becattini B, Kitada S, Leone M, et al: Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol. 11:389–395. 2004. View Article : Google Scholar : PubMed/NCBI
43	Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M and Reed JC: Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048). Blood. 111:3211–3219. 2008. View Article : Google Scholar : PubMed/NCBI
44	Coward L, Gorman G, Noker P, et al: Quantitative determination of apogossypol, a proapoptotic analog of gossypol, in mouse plasma using LC/MS/MS. J Pharm Biomed Anal. 42:581–586. 2006. View Article : Google Scholar : PubMed/NCBI
45	Sattler M, Liang H, Nettesheim D, et al: Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science. 275:983–986. 1997. View Article : Google Scholar : PubMed/NCBI
46	Eldridge MD, Murray CW, Auton TR, Paolini GV and Mee RP: Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des. 11:425–445. 1997. View Article : Google Scholar : PubMed/NCBI
47	Ramjaun AR, Tomlinson S, Eddaoudi A and Downward J: Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene. 26:970–981. 2007. View Article : Google Scholar
48	Katsumata M, Siegel RM, Louie DC, et al: Differential effects of Bcl-2 on T and B cells in transgenic mice. Proc Natl Acad Sci USA. 89:11376–11380. 1992. View Article : Google Scholar : PubMed/NCBI