Empirical Study Of Curcumin Anti-cervical Carcinoma Effect And Its Mechanism

Charpter I The curry spice curcumin selectively inhibits cancer cells growth in vitro and in preclinical model of cervical carcinomaPrevious studies suggested that curcumin is a potential agent against cervical carcinoma. However, the in vivo efficacy of curcumin in cervical carcinoma remains not established. In this work, we examined the mechanisms underlying apoptosis, selectivity, efficacy and safety of curcumin from in vitro (SiHa,Caski,HeLa-S3and HeLa229cell lines) and in vivo (SiHa implants) models of cervical carcinoma. In vitro, curcumin markedly inhibited proliferation and migration and induced cell death in liquid and soft agar models of cervical carcinoma growth. Curcumin effects occurred irrespective of the p53and PTEN mutational status of the cells. Interestingly, curcumin did not affect viability of primary astrocytes, suggesting that curcumin selectivity targeted transformed cells. In Caski and SiHa cells, curcumin decreased the constitutive activation of PI3K/Akt and NFkappaB survival pathways, down-regulated the antiapoptotic NFkappaB-regulated protein bcl-xl and induced mitochondrial dysfunction as a prelude to apoptosis. Cells developed an early G2/M cell cycle arrest followed by sub-G1apoptosis and apoptotic bodies formation. Caspase-3activation occurred in the p53-normal cell type SiHa, but not in the p53-mutant Caski. Besides its apoptotic effect, curcumin also synergized with the chemotherapeutics cisplatin and doxorubicin to enhance cervical carcinoma cells death. In SiHa-implanted rats, intraperitoneal curcumin (50mg kg-1/d-1) decreased cervical tumors in9/11(81.8%) animals against0/11(0%) in the vehicle-treated group. Importantly, no evidence of tissue (transaminases, creatinine and alkaline phosphatase), metabolic (cholesterol and glucose), oxidative or hematological toxicity was observed. In summary, data presented here suggest curcumin as a potential agent for therapy of cervical carcinoma. Charpter Ⅱ Beneficial effects of curcumin on antitumor activity and adverse reactions of doxorubicinMany medicines used in cancer chemotherapy decrease the quality of life (QOL). It is believed that an increase in food intake during cancer chemotherapy may produce an improvement in QOL. Curcumin is widely used as a coloring and flavoring agent in food. The effects of curcumin in relation to the chemotherapeutic drug doxorubicin (DOX) were examined. While DOX alone did not decrease tumor weight, the combination of DOX and curcumin significantly reduced tumor weight to56.5%(p<0.05) of that of the control group. The combined curcumin enhanced apoptosis by DOX and decreased cell viability. The curcumin-DOX combination also suppressed activation of caspase-3,-8, and-9compared to DOX alone. It is presumed that combining curcumin increased DOX-induced antitumor activity by suppressing the main caspase pathway and activating the main caspase independent pathway. The combination of curcumin and DOX suppressed the reduction of glutathione peroxidase activity and increased lipid peroxide levels in the heart. Therefore, it is expected that curcumin may reduce the adverse reactions associated with DOX. Our results suggest that curcumin can be used as a modulator to enhance the therapeutic index of cancer patients and improve their QOL Charpter III Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2via promoter CpGs demethylationCervical carcinoma is one of the most deadly malignancies among women in the world. Although localized Cervical carcinomar can be effectively treated via surgery or radiation, metastatic disease is usually lethal. Recent evidence suggests that the development and progression of humanCervical carcinoma involves complex interplay between epigenetic alterations and genetic defects. We have recently demonstrated that Nrf2, a master regulator of cellular antioxidant defense systems, was epigenetically silenced during the progression of Cervical carcinoma tumorigenesis in Caski mice. The aim of this study is to investigate the potential of curcumin (CUR), a dietary compound that we have reported to be able to prevent the development of Cervical carcinoma in Caski mice, as a DNA hypomethylation agent. Using bisulfite genomic sequencing (BGS), treatment of TRAMP C1cells we showed that CUR reversed the methy lation status of the first5CpGs in the promoter region of the Nrf2gene. Methylation DNA immunoprecipitation (MeDIP) analysis revealed that CUR significantly reduced the anti-mecyt antibodybinding to the first5CpGs of the Nrf2promoter, corroborated the BGS results. Demethylation of Nrf2was found to be associated with the re-expression of Nrf2and one of its downstream target gene, NQO-1, one of the major anti-oxidative stress enzymes, both at the mRNA and protein levels. Taken together, our current study suggests that CUR can elicit its prostate cancer chemopreventive effect, potentially at least in part, through epigenetic modification of the Nrf2gene with its subsequent induction of the Nrf2-mediated anti-oxidative stress cellular defense pathway.