The Target Differences of Anti-Tumorigenesis Potential of Curcumin and its Analogues Against HER-2 Positive and Triple-Negative Breast Cancer Cells.

Purpose: The current study aims to evaluate the in vitro cytotoxic and cell migration effects of synthetic curcumin and its analogues on HER2 and nuclear factor kappa B (NFκB) pathways, as well as the in vivo inhibitory effect on cancer growth of metastatic breast cancer. Methods: Cell viability, protein expression, and protein localization were determined in vitro using MTT assay, western blotting, and immunofluorescence, respectively. Meanwhile, scratch wound healing assay and gelatin zymography were conducted to investigate the metastasis inhibitory effect. The in vivo anti-tumor ability was evaluated in xenograft mouse model using triple-negative breast cancer (TNBC) cells. Results: Curcumin, PGV-0, and PGV-1 exhibited cytotoxic effect against HER2-overexpressing breast cancer cells. Although PGV-1 showed the best activity in the single cytotoxic assay, curcumin showed the strongest synergism with doxorubicin. Curcumin and PGV-0 inhibited membrane localization of HER2. In contrast, PGV-1 neither inhibited localization nor decreased the expression of HER2, nonetheless showed the most potent inhibition against nuclear localization of p65 indicating the different mechanisms of curcumin, PGV-0, and PGV-1. Regarding cancer metastasis, curcumin and PGV-1 showed inhibitory activities against cell migration and inhibited MMP-2 and MMP-9 protein expression. Lastly, PGV-1 was more potent compared to curcumin to suppress the tumor formation of metastatic breast cancer xenograft model in nude mice. Conclusion: Overall, our study strengthens the potency of curcumin analogue, PGV-1, for treating several types of cancer, including metastatic breast cancer.

The Chemopreventive Activity of Indonesia Medicinal Plants Targeting on Hallmarks of Cancer.

Cancer remains a complex disease with increasing global mortality and morbidity. Numerous theories have been established to understand the biological mechanism underlying cancer. One of the most renowned frameworks is the hallmark of cancer proposed by Hanahan and Weinberg that covers ten eminent characteristics of cancer: (i) genome instability and mutation, (ii) sustaining proliferative signaling, (iii) evading growth suppressor, (iv) enabling replicative immortality, (v) resisting cell death, (vi) inducing angiogenesis, (vii) activating invasion and metastasis, (viii) avoiding immune destruction, (ix) tumor-promoting inflammation, and (x) deregulating cellular energetics. These hallmarks provide a rational approach to design an anticancer therapy. In the current review, we summarized specific target molecules on each hallmark of cancer. Further, we evaluated the biological activity of several Indonesia medicinal plants against those specific targets. We explicated the anticancer and chemopreventive activities of some medicinal plants that have been used for centuries by local communities in Indonesia, including Curcuma genus, Brucea javanica, Boesenbergia pandurata, Caesalpinia sappan, and Nigella sativa. Interestingly, these medicinal plants target several hallmarks of cancer, and even Curcuma genus exhibited biological activities that target all hallmarks of cancer. Further, we also discuss several strategies to develop those medicinal plants and/or their active compounds as anticancer and chemopreventive agents.

Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth.

Curcumin has been reported to exhibit anti-tumorigenic activity; however, since its precise actions remain unclear, its effects are considered to be deceptive. In the present study, we confirmed the anti-tumorigenic effects of curcumin on CML-derived leukemic cells in a xenograft model and in vitro culture system. In vitro pull-down and mass analyses revealed a series of enzymes (carbonyl reductase, glutathione-S-transferase, glyoxalase, etc.) that function in a reactive oxygen species (ROS) metabolic pathway as curcumin-binding targets, the expression of which was up-regulated in human leukemia. Curcumin increased ROS levels over the threshold in leukemic cells, and the antioxidant, glutathione (GSH) and overexpression of curcumin-binding enzymes partially mitigated the up-regulation of ROS and growth inhibition caused by curcumin. These results show that curcumin specifically inhibits tumor growth by increasing ROS levels over the threshold through the miscellaneous inhibition of ROS metabolic enzymes. Curcumin has potential in therapy to regulate ROS levels in tumor cells, thereby controlling tumor growth.

Curcumin Analog Pentagamavunon-1 (PGV-1) Sensitizes Widr Cells to 5-Fluorouracil through Inhibition of NF-κB Activation

Cell cycle regulation and the NF-κB pathway in cancer cells are important in mediating resistance to 5-Fluorouracil (5-FU). Pentagamavunon-1 (PGV-1), a curcumin analog, is known to exhibit stronger growth inhibitory effects than curcumin itself in several cancer cells. In this study, we evaluated the potency of PGV-1 in combination with 5-FU in WiDr colon cancer cells. In MTT assays, PGV-1 did not only exhibit stronger growth inhibitory effects than both 5-FU and curcumin, but also enhanced the cytotoxicity of 5-FU. Flow cytometry demonstrated that single treatments with PGV-1 and 5-FU resulted in different effects on cell cycle profiles. PGV-1 induced G2/M arrest while 5-FU caused S-phase arrest at low concentration (1 µM) and G1-phase arrest at high concentration (100 µM). Interestingly, the combination of 5-FU and PGV-1 enhanced cell accumulation in S-phase. Although a single treatment with either 5-FU or PGV-1 increased cyclin D1 at the protein level, the combination treatment resulted in significant suppression. In addition, PGV-1 inhibited activation of NF-κB and suppressed the expression of cyclooxygenase-2, an NF-κB downstream protein. In conclusion, PGV-1 increased the cytotoxic effect of 5-FU on WiDr cells through inhibition of NF-κB activation.

Cardioprotective and hepatoprotective effects of Citrus hystrix peels extract on rats model.

OBJECTIVE: To observe the combination effect of doxorubicin and Citrus hystrix (kaffir lime's) peel ethanolic extract (ChEE) on blood serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity and cardio-hepato-histopathology of female Sprague Dawley rats. METHODS: Doxorubicin and ChEE (5 rats per group) were administered in five groups of 3 rats each for 11 d. Group I: doxorubicin (dox) 4.67 mg/kg body weight; Group II: dox+ChEE 500 mg/kg body weight; Group III: dox+ChEE 1 000 mg/kg body weight; Group IV: ChEE 1 000 mg/kg body weight; Group V: untreated (control). RESULTS: ChEE repaired cardiohistopathology profile of doxorubicin induced cardiotoxicity and hepatotoxicity rats, but did not repair neither hepatohistopathology profile nor reduce serum activity of ALT and AST. CONCLUSION: ChEE has potency to be developed as cardioprotector agent in chemotherapy.