apogossypol and Prostatic-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 8; Cell Line, Tumor; Cell Proliferation; Female; Gossypol; Humans; Male; Mice, Nude; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2

Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.

Topics: Adenoviridae; Animals; Antineoplastic Agents; Apoptosis; Biological Mimicry; Cell Line, Tumor; Cysteine-Rich Protein 61; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Gossypol; Humans; Interleukins; Male; Mice, Nude; Mice, Transgenic; Myeloid Cell Leukemia Sequence 1 Protein; Oncolytic Virotherapy; Oncolytic Viruses; Peptide Fragments; Promoter Regions, Genetic; Prostatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Rats; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for mda-7/IL-24-mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to mda-7/IL-24-induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize mda-7/IL-24-mediated cytotoxicity. A combination regimen of tropism-modified adenovirus delivered mda-7/IL-24 (Ad.5/3-mda-7) and BI-97C1 enhances cytotoxicity in human PC cells, including those resistant to mda-7/IL-24 or BI-97C1 alone. The combination regimen causes autophagy that facilitates NOXA- and Bim-induced and Bak/Bax-mediated mitochondrial apoptosis. Treatment with Ad.5/3-mda-7 and BI-97C1 significantly inhibits the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. Tumor growth inhibition correlated with increased TUNEL staining and decreased Ki-67 expression in both PC xenografts and prostates of Hi-myc mice. These findings demonstrate that pharmacological inhibition of Mcl-1 with the Apogossypol derivative, BI-97C1, sensitizes human PCs to mda-7/IL-24-mediated cytotoxicity, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Genetic Therapy; Gossypol; Humans; Interleukins; Male; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Transfection; Xenograft Model Antitumor Assays