Abstract
Cervical cancer is one of the most common cancers among women worldwide. Current standards of care for cervical cancer includes surgery, radiation, and chemotherapy. Conventional chemotherapy fails to elicit therapeutic responses and causes severe systemic toxicity. Thus, developing a natural product based, safe treatment modality would be a highly viable option. Curcumin (CUR) is a well-known natural compound, which exhibits excellent anti-cancer potential by regulating many proliferative, oncogenic, and chemo-resistance associated genes/proteins. However, due to rapid degradation and poor bioavailability, its translational and clinical use has been limited. To improve these clinically relevant parameters, we report a poly(lactic-co-glycolic acid) based curcumin nanoparticle formulation (Nano-CUR). This study demonstrates that in comparison to free CUR, Nano-CUR effectively inhibits cell growth, induces apoptosis, and arrests the cell cycle in cervical cancer cell lines. Nano-CUR treatment modulated entities such as miRNAs, transcription factors, and proteins associated with carcinogenesis. Moreover, Nano-CUR effectively reduced the tumor burden in a pre-clinical orthotopic mouse model of cervical cancer by decreasing oncogenic miRNA-21, suppressing nuclear β-catenin, and abrogating expression of E6/E7 HPV oncoproteins including smoking compound benzo[a]pyrene (BaP) induced E6/E7 and IL-6 expression. These superior pre-clinical data suggest that Nano-CUR may be an effective therapeutic modality for cervical cancer.
Highlights
Cervical cancer is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection[1]
A recent proteomic study suggests that curcumin induces significant changes in tumor-related proteins that are associated with cell metabolism, cell cycle, and carcinogenicity in HeLa cells[15]
Our study demonstrated that curcumin inhibited cell motility, induced apoptosis, decreased the expression of HPV oncoproteins, and restored tumor suppressor proteins
Summary
Cervical cancer is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection[1]. To circumvent curcumin’s inherent issues, our lab has developed a curcumin nanoparticle formulation (Nano-CUR), (Fig. 1A,B) based on poly(lactic-co-glycolic acid) (PLGA), an FDA approved polymer This formulation has shown to be effective for improved therapeutic effects in metastatic ovarian and breast cancer cells[22]. Nano-CUR treatment caused a marked decrease in the levels of miRNA-21 (an onco-miRNA associated with chemo-resistance), in in vitro and in vivo models[23,24], and enhanced the expression of miRNA-214 (a tumor suppressor)[25,26], when compared to free CUR, besides decreasing the levels of IL-6 (Interleukin-6) cytokine expression which was found to be enhanced with BaP treatment These results suggest that Nano-CUR provides a beneficial approach for a rational strategy to widen the chemo-preventive and therapeutic modality for the overall management of cervical cancer
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