Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth

Abstract

Background Prostate cancer (PCa) remains the second leading cause of cancer‐related death among men. Taxanes, such as docetaxel and cabazitaxel are utilized in standard treatment regimens for chemotherapy naïve castration‐resistant PCa. However, tumors often develop resistance to taxane chemotherapeutics, highlighting a need to identify additional therapeutic targets. Fatty acid‐binding protein 5 (FABP5) is an intracellular lipid carrier whose expression is upregulated in metastatic PCa and increases cell growth, invasion, and tumor formation. Here, we assessed whether FABP5 inhibitors synergize with semi‐synthetic taxanes to induce cytotoxicity in vitro and attenuate tumor growth in vivo. Methods PC3, DU‐145, and 22Rv1 PCa cells were incubated with FABP5 inhibitors Stony Brook fatty acid‐binding protein inhibitor 102 (SBFI‐102) or SBFI‐103 in the presence or absence of docetaxel or cabazitaxel, and cytotoxicity was evaluated using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5 diphenyl tetrazolium bromide assay. Cytotoxicity of SBFI‐102 and SBFI‐103 was also evaluated in noncancerous cells. For the in vivo studies, PC3 cells were subcutaneously implanted into BALB/c nude mice, which were subsequently treated with FABP5 inhibitors, docetaxel, or a combination of both. Results SBFI‐102 and SBFI‐103 produced cytotoxicity in the PCa cells. Coincubation of the PCa cells with FABP5 inhibitors and docetaxel or cabazitaxel produced synergistic cytotoxic effects in vitro. Treatment of mice with FABP5 inhibitors reduced tumor growth and a combination of FABP5 inhibitors with a submaximal dose of docetaxel reduced tumor growth to a larger extent than treatment with each drug alone. Conclusions FABP5 inhibitors increase the cytotoxic and tumor‐suppressive effects of taxanes in PCa cells. The ability of these drugs to synergize could permit more efficacious antitumor activity while allowing for dosages of docetaxel or cabazitaxel to be lowered, potentially decreasing taxane‐resistance.

Downregulation of FABP5 Suppresses the Proliferation and Induces the Apoptosis of Gastric Cancer Cells Through the Hippo Signaling Pathway

“…Accumulating evidence has demonstrated that FABP5 is involved in the progression of malignant tumors, which highlights the oncogenic role of FABP5 (Apaya et al, 2020;Carbonetti et al, 2020;Seo et al, 2020;Zhang et al, 2020). In this study, we found that high FABP5 expression indicated poor prognosis of GC patients.…”

Combination Treatment Options for Castration-Resistant Prostate Cancer

“…Efforts have continued on developing new compounds and combinations. As for pre-clinical models, the combination of fatty acid binding protein 5 (FABP5) inhibitors and docetaxel or cabazitaxel shows synergistic cytotoxic effects in vitro and in vivo (75). Similarly, docetaxel nanoparticles in combination with the receptor activator of nuclear factor κB ligand (RANKL) monoclonal antibody, denosumab, led to an increase in survival and reduction in tumor burden and bone metastasis in prostate cancer xenograft animal model (76).…”

How cancer cells remodel lipid metabolism: strategies targeting transcription factors

“…dmrFABP5 significantly suppresses proliferation, migration, and invasion of prostate cancer cells [ 172 ]. SBFI-102 and SBFI-103 increase cytotoxicity in prostate cancer cells and stimulate tumor-suppressive effects of other chemicals, taxanes [ 173 ]. EI-05, FABP5 activator, enhances lipid droplet and interferon-β production, which further promotes the anti-tumor activity of macrophages during inflammation.…”