Abstract
BackgroundCurrent chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation.MethodsProstate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software.ResultsDocetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells.ConclusionCombination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.
Highlights
Current chemotherapy for castration-resistant prostate cancer is established on taxane-based com‐ pounds like docetaxel
Capsaicin and docetaxel synergistically inhibit prostate cancer cells growth To assess the antiproliferative effect of docetaxel (DTX) and capsaicin (CAP), prostate cancer LNCaP and PC3 cells were incubated with increasing doses of DTX, CAP or the combination of both compounds and cell viability was determined by MTT
Combination-index showed a potent synergy of cell killing at four of the five combinations used in LNCaP cells and at the five combinations used for PC3 cells
Summary
Current chemotherapy for castration-resistant prostate cancer is established on taxane-based com‐ pounds like docetaxel. The development of toxic side effects and resistance limits the thera‐ peutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treat‐ ment of castration-resistant prostate cancer. Docetaxel is the first-line chemotherapeutic agent available to patients with this lethal form of the disease, but the survival of patients remains limited by the occurrence of dose-dependent adverse effects and acquired resistance. It is of highly clinical significance to identify agents that when combined with the current chemotherapeutic drugs allow to decrease the doses without reducing their effectiveness as well as to avoid and/or to overcome drug resistance. Combination therapy, a treatment modality that combines two or more therapeutic agents, is becoming a cornerstone of cancer therapy [5]
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