Effects of Curcumin Analogues for Inhibiting Human Prostate Cancer Cells and the Growth of Human PC-3 Prostate Xenografts in Immunodeficient Mice

Abstract

Four curcumin analogues ((2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (2E,5E)-2,5-bis(thiophen-3-methylene) cyclopentanone (BS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydropyran-4-one (ES) and (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4-one (FS) as shown in Fig. 1) with different linker groups were investigated for their effects in human prostate cancer CWR-22Rv1 and PC-3 cells. Compounds FS and ES had stronger inhibitory effects than curcumin, AS and BS on the growth of cultured CWR-22Rv1 and PC-3 cells, as well as on the androgen receptor (AR) and nuclear factor kappa B (NF-κB) activity. The strong activities of ES and FS may be correlated with a heteroatom linker. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously (s.c.) with PC-3 cells in Matrigel. After 4 to 6 weeks, mice with PC-3 tumors (about 0.6 cm wide and 0.6 cm long) received daily intraperitoneal (i.p.) injections of vehicle, ES and FS (10 µg/g body weight) for 31 d. FS had a potent effect in inhibiting the growth and progression of PC-3 tumors. Our results indicate that FS may be useful for inhibiting human prostate tumors growth. Key words curcumin analog; prostate cancer cell; prostate tumorProstate cancer is one of the leading causes of death among men in the United States.1) Prostate carcinogenesis has been viewed as a multistage and complex process consisting of initiation, promotion, and progression. Despite the tremendous efforts and resources devoted to treatment, incidence and mortality rate are still high. Although patients with metastatic prostate cancer can benefit from androgen ablation, most of them will die of prostate cancer progression due to an androgen-refractory state. Hence, much attention has been paid to the discovery of chemopreventive substances from various edible and medicinal plants, a large number of which have been identified.Curcumin is a non-nutritive yellow pigment found in the spice turmeric, which is derived from the rhizome of the plant Curcuma longa LINN. Numerous studies have demonstrated the anticancer activity of curcumin and curcumin analogues in animal models 2-7) as well as growth inhibition and apoptosis induction in a variety of cancer cell lines in vitro. [8][9][10][11][12][13][14][15][16] However, the clinical efficacy of curcumin is limited, which is likely due to its low bioavailability. [17][18][19] We have previously reported on the synthesis and evaluation of sixty-one curcumin-related compounds for inhibitory effects on cultured prostate cancer cells, pancreatic cancer cells and colon cancer cells. 20) Four of these curcumin analogues with different linker groups but identical symmetrical aromatic rings (as shown in Fig. 1) were selected for the present study. These compounds included (2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (2E,5E)-2,5-bis(thiophen-3-methylene) cyclopentanone (BS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydropyran-4-one (ES), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4...

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

“…The present study identified that analogues with tetrahydrothiopyran-4-one (FN) as the linker were more potent inhibitors than those with tetrahydropyran-4-one (EN), cyclohexanone (AN) or cyclopentanone (BN). Earlier studies revealed that the six-membered cyclohexanone ring system is, in general, superior to the five-membered cyclopentanone system for inhibiting the growth of several cancer cell lines (23,24). The current results confirmed this structure activity association, as pyridine cyclohexanone curcumin analogues displayed stronger inhibitory activities than pyridine cyclopentanone curcumin analogues.…”

“…Our previous study and another previous study indicated that cyclohexanone-containing analogues of curcumin have more potent anticancer activities than curcumin (23,24). Further modification of cyclohexanone-containing curcumin analogues by replacing the ortho-hydroxylmethoxyl benzene with a pyridine ring strongly enhanced the anticancer activities of these curcumin analogues (23).…”

FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway

“…To circumvent these problems, numerous analogs of curcumin have been synthesized. For example, the potential activity of recently synthesized curcumin analogs (2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4-one (FS), A501, and GO-Y031 has been studied in prostate cancers, NSCLC cells and gastric cancers [14–16]. …”

Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells

“…; resveratrol, a polyphenolic stilbene found in grapes; silibinin, a naturally-occurring flavonoid produced by milk thistle and melatonin, an indole that is mainly produced by the pineal gland in vertebrates but also found in edible plants [18], was investigated. All of them have shown effects against tumor growth in cells or in rodent models of prostate cancer [19], [20], [21], though, the molecular pathways involved in their mechanisms of action, in particular the redox signaling pathways altered, still remain unclear. In this study, we aim to investigate ROS-mediated apoptosis signaling pathways induced by these bioactive compounds that have displayed antioxidant or pro-oxidant activities in vitro [22], [23], [24], [25].…”