Cyclohexanone curcumin analogs inhibit the progression of castration‐resistant prostate cancer in vitro and in vivo

Abstract

Many prostate cancer patients develop resistance to treatment called castration‐resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti‐metastasis properties and found that 2,6‐bis‐(4‐hydroxy‐3‐methoxy‐benzylidene)‐cyclohexanone (2A) and 2,6‐bis‐(3,4‐dihydroxy‐benzylidene)‐cyclohexanone (2F) showed higher anti‐invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP‐2 and MMP‐9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10‐bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo.

Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo

“…In agreement with the findings of previous studies, Cur displayed higher levels of in vitro cytotoxicity against lung [20] and colon cancers than DZG [16]. Our previous study showed the IC 50 of Cur on PLS10 cells was 26.50 ± 1.80 µM, which was similar with this study [21]. This study confirmed that Cur induced G1 phase arrest via the inhibition of cyclin D1 expression in PLS10 cells, which is similar to the DZG treatment (Figure 3).…”

“…In our previous studies involving the cyclohexanone Cur analog, the replacement of β-diketone with the cyclohexanone group did not improve the pharmacokinetics of Cur [21]. However, in this study, we used DZG with a lack of β-diketone moiety (no other functional group replacements) and found that DZG could improve the pharmacokinetics and tissue distribution of Cur.…”

“…Notably, in previous studies on colon cancer, HT-29 cells found that DZG in the concentration range of 250-500 µM suppressed the proliferation of HT-29 cells via induction of the cell cycle arrest in the G2/M phase [16]. Numerous published studies also reported that Cur, and its analogs, initiated cancer cell cycle arrest in both G1 and G2/M phases, depending on the type of cancer [21][22][23].Taken together, these findings suggest that DZG and Cur suppressed PLS10 cells proliferation via the inhibition of cyclin D1 expression, leading to cell cycle arrest in the G1 phase.…”

“…injection. Therefore, in this experiment, the same concentrations of Cur and DZG were performed and compared with the efficacy in the xenograft model [21]. In addition, the DZG concentrations up to 100 mg/kg body weight showed no toxicity [24].…”

Hexane Insoluble Fraction from Purple Rice Extract Retards Carcinogenesis and Castration-Resistant Cancer Growth of Prostate Through Suppression of Androgen Receptor Mediated Cell Proliferation and Metabolism

“…In addition to anti-proliferative and anti-apoptotic effects, anti-angiogenesis is one of the underlying mechanisms that can suppress the tumor growth and progression [28]. A range of natural or synthetic compounds inhibits cancer metastasis by blocking the formation of blood vessels [24,29,30]. In this study, the effect of PRE-HIF on the vessel numbers was not observed in PCai1 tumor.…”