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.
Screening prostatic carcinogens is time-consuming due to the time needed to induce preneoplastic and neoplastic lesions. To overcome this, we investigated alternative molecular markers for detection of prostatic carcinogens in a short period in rats. After treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), expression of high-mobility group protein B2 (HMGB2) was upregulated in rat ventral prostate. To evaluate the applicability of HMGB2 in the early detection of carcinogenicity of chemicals using animal models, we examined HMGB2 expression in prostate of rats. Six-week-old male F344 rats were gavaged for four weeks with a total of eight individual chemicals, divided into two categories based on prostate carcinogenicity. Animals were sacrificed at the end of the study and HMGB2 immunohistochemistry was performed. HMGB2 expression in least one prostate lobe was significantly increased by all four prostate carcinogens compared with the controls. In contrast, the four chemicals that were not carcinogenic in the prostate did not cause HMGB2 up-regulation. Additionally, high HMGB2 expression in neoplastic lesions in both rat and human was detected. Therefore HMGB2 expression may be a good screening tool for the identification of potential of prostate carcinogens.
Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.
Reactive oxygen species (ROS) have been revealed to be important factors for carcinogenesis and tumor progression. Therefore, we focused on an ROS-generating protein, nicotinamide adenine dinucleotide phosphate oxidase, and evaluated whether its inhibitor, apocynin, could suppress hepatocarcinogenesis in a medium-term rat liver bioassay. The number and size of glutathione S-transferase placental form (GST-P)-positive foci were significantly reduced by apocynin in a dose-dependent manner. The reduction of ROS generation by apocynin was confirmed by dihydroethidium staining. Apocynin treatment also significantly reduced Ki-67 positivity, downregulated cyclooxygenase 2, and suppressed the activation of the c-Myc pathway. Meanwhile, ROS generation was not different between GST-P-positive foci and surrounding GST-P-negative areas of the liver. In conclusion, the present data suggest that apocynin possesses a potential antihepatocarcinogenic property.
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