Abstract A57: Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment

Abstract

Abstract Underserved populations such as African Americans (AA) and American Indians (AI) are experiencing increasing prevalence and mortality rates of cervical cancer (CxCa) as compared to Caucasians (CA). CxCa is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection. A persistent oncogenic HPV infection itself is not enough to immortalize and transform the epithelial host cell, as over a course of time only a small proportion of women with chronic HPV infection progress to develop disease. Additional factors are needed to acquire an immortal, malignant and invasive phenotype. In addition to HPV infection, cigarette smoking is a known risk factor. Polycyclic aromatic hydrocarbons (PAHs), such as Benzo[a]pyrene (BaP), are among the numerous carcinogens associated with cigarette smoking. The level of BaP has been found to be elevated in the cervical mucus of women who smoke. Moreover, a number of studies have implicated BaP to affect both the viral life cycle and the cellular environment. BaP has been shown to stimulate high levels of virion synthesis in cell lines prolifically infected with HPV. Furthermore, in other cancers the primary metabolite of BaP, benzo(a)pyrene diol epoxide increases the expression of oncogenic transcription factors like NFκB and oncogenic cytokines such as Interleukin-6 (IL-6). IL-6 in turn is known to activate transcription factors such as STAT3 and enhance the malignant transformation of cells. This is achieved through the transcriptional activation of oncogenic microRNAs (miRNA) like miRNA-21. MiRNAs are small non-coding RNAs that regulate gene expression and their aberrant regulation/function has been reported in a large majority of cancers. miRNA-21 has been shown to enhance chemoresistance to established regimens of chemotherapy and radiation therapy. This resistance to chemo-radio therapy with prolonged treatment, resulting in an invasive form of cancer, requires the development of novel therapeutic modalities to conquer chemo resistance and improve overall life expectancy of patients. Nanotechnology provides targeted delivery of anti-cancer drugs and indicates a new approach for cancer diagnosis and treatment. Our lab has developed PLGA (poly [lactic-co-glycolic acid]), an FDA approved polymer coated nanoparticle(s) using a well-known anti-cancer drug Curcumin (Cur) for the enhanced bioavailability and improved therapeutic efficacy of Cur, known as nano-curcumin (NC). In comparison to pure Cur, NC effectively inhibited Caski/ SiHa cell growth and also induced apoptosis as determined by staining for Annexin V/7AAD. PI staining revealed that NC treatment arrests growth cycle of Caski/SiHa cells in the G2-M phase. Additionally, NC treatment caused a marked decrease in the levels of miRNA 21, an oncomiRNA associated with chemoresistance, and enhanced by BaP, with a concomitant increase in the tumor suppressor miRNA-214 (decreased by BaP). It was found to down-regulate the expression of oncogenic proteins and cytokines such as IL-6 and enhance the expression of tumor suppressor entities as evident from Western blots. Moreover, NC formulation effectively reduced the tumor burden in Non SCID gamma mice. Furthermore, it decreased the expression of oncogenic miRNA-21 in in vivo experiments as observed through ISH. Our findings show that PLGA based NC significantly inhibits Caski/SiHa CxCa cell tumorigenicity and regulates the expression of miRNAs, associated with CxCa. In vivo experiments show that NC is efficacious in reducing the tumor burden. Therefore, NC may be a novel chemo-preventive and therapeutic modality for the overall management of CxCa. Citation Format: Mohd Saif Zaman, Neeraj Chauhan, Diane Maher, Rishi Gara, Mohammed Sikander, Murali Mohan Yallapu, Sheema Khan, Meena Jaggi, Subhash Chauhan. Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A57.