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

Abstract

Many prostate cancer patients develop resistance to the treatment called castration‐resistant prostate cancer (CRPC), which is the major cause of recurrence and death. In this study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anti‐cancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti‐metastasis property and found that 2,6‐bis‐(4‐hydroxy‐3‐methoxy‐benzylidene)‐cyclohexanone (2A) and 2,6‐bis‐(3,4‐dihydroxy‐benzylidene)‐cyclohexanone (2F) exhibited 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 MMPs activities. These findings suggest that the compounds may inhibit CRPC cell metastasis via decreased extra cellular matrix degradation. Analog 2A, the most potent analog, was then subjected to the in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 min after intraperitoneal injections. Analog 2A and curcumin (30 mg/Kg BW) showed a similar ability to reduce tumor area in lungs of mice that were intravenously injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 growth via induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with the down‐regulation 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.

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