Pyridine analogues of curcumin exhibit high activity for inhibiting CWR-22Rv1 human prostate cancer cell growth and androgen receptor activation

Abstract

Abstract. The concentrations required for curcumin to exert its anticancer activity (IC 50 , 20 µM) are difficult to achieve in the blood plasma of patients, due to the low bioavailability of the compound. Therefore, much effort has been devoted to the development of curcumin analogues that exhibit stronger anticancer activity and a lower IC 50 than curcumin. The present study investigated twelve pyridine analogues of curcumin, labeled as groups AN, BN, EN and FN, to determine their effects in CWR-22Rv1 human prostate cancer cells. The inhibitory effects of these compounds on testosterone (TT)-induced androgen receptor (AR) activity was determined by performing an AR-linked luciferase assay and by TT-induced expression of prostate-specific antigen.The results of the current study suggested that the FN group of analogues had the strongest inhibitory effect of growth on CWR-22Rv1 cultured cells, and were the most potent inhibitor of AR activity compared with curcumin, and the AN, BN and EN analogues. Thus, the results of the present study indicate the inhibition of the AR pathways as a potential mechanism for the anticancer effect of curcumin analogues in human prostate cancer cells. Furthermore, curcumin analogues with pyridine as a distal ring and tetrahydrothiopyran-4-one as a linker may be good candidates for the development of novel drugs for the treatment of prostate cancer, by targeting the AR signaling pathway. IntroductionProstate cancer is the second most common cause of cancer-related mortality in American men. The androgen receptor (AR) is a ligand-activated steroid hormone receptor that regulates normal prostate development and function (1). It is also critical in the development and progression of prostate cancer (2). Current therapeutic strategies for prostate cancer, such as androgen ablation therapy, inhibit AR function (3). A combination of androgen synthesis suppression and AR inhibition may be used as a more aggressive form therapy (4). Therefore, identification of the chemical agents and mechanisms that inhibit AR signaling warrant further investigation for the development of novel prostate cancer therapeutics.Curcumin is a non-nutritive yellow pigment found in turmeric, a rhizome-derivative of the plant Curcuma longa Linn. Numerous studies have demonstrated the anticancer activity of curcumin and curcumin analogues in animal models (5-10), as well as the effects on cell growth and apoptosis in vitro (11)(12)(13)(14)(15)(16)(17)(18)(19). However, it should be noted that the clinical efficacy of curcumin is limited, possibly due to its low bioavailability (20)(21)(22).In our previous study, we synthesized a series of 12 pyridine analogues of curcumin with cyclohexanone, cyclopentanone, tetrahydropyran-4-one or tetrahydrothiopyran-4-one linkers, and determined their anticancer activities in cultured human cancer cells (23). It was determined that these pyridine analogues exhibited stronger inhibitory effects than curcumin on the growth of a number of human cancer cell lines, including human pros...

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Curcumin and Its Derivatives as Potential Therapeutic Agents in Prostate, Colon and Breast Cancers

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The potential role of curcumin in prostate cancer: the importance of optimizing pharmacokinetics in clinical studies

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