Abstract 4020: Identification and characterization of Novel MYC and p53 target molecules from medicinal plants of North East India

Abstract Background: Identification and characterization of novel molecular inhibitors that target key regulators of cancer stem cell (CSCs) self-renewal is promising in cancer therapeutics. MYC and p53, the two major cellular transcription factors, acts as key molecular regulators in stem cells and cancer stem cells self-renewal. While MYC enhances, p53 inhibits the self-renewal of stem cells. Thus, developing novel molecules that could potentially target either MYC and or p53 might potential therapeutic application. However, the search for small molecules that could target the self-renewal aspect of these two proteins has been elusive. Previously; we demonstrated that isoprenoid molecule squalene could enhance bone marrow hematopoietic and mesenchymal stem cells (MSCs) by modulating MYC. Importantly, we found that ursolic acid, an isoprenoid molecule found in Tulsi plant, inhibited HIF-1alpha, a transcription factor regulated by MYC and p53. Hence, having these prior experiences on isoprenoids, we speculate that novel isoprenoid may exist that could modulate MYC’s role in cancer self-renewal. We are especially interested in identifying novel isoprenoid molecules (metabolites of mevalonate pathway) found in medicinal plants of North East India, where KaviKrishna laboratory is located. Methods: For the study, we proposed to develop an in vitro self-renewal based assay platform(henceforth known as STEM-TECH platform) to identify novel molecules that act on self-renewal aspect of MYC and p53. In this assay, we subjected the oral cancer cell line SCC-25 to 3-D tumoringeic growth using methylcellulose based method. Using this assay, we have screened 20 herbal extracts of North East India, and selected 3 herbal extracts for further evaluation. For the in vivo study, we added these herbal extracts to drinking water of C57BL/6 mice treated with 4NQO (an oral carcinogen) and FVB/N mice with MYC-induced thymic lymphoma. The mice were observed for 10 weeks and subjected to evaluation of tumor growth, and also evaluation of cancer stem cells using ABCG2, a cell surface marker expressed by cancer stem cells. Results: We found that herbal extracts from Tulsi and Soalu exhibited strong anti-tumor activity in the in vivo mouse models. Importantly, these extracts exhibited the ability to inhibit the self-renewal of MYC driven ABCG2+ cancer cells (1). Also, these extracts were then subjected to in vitro Stem-Tech assay and we found that one herbal extract could modulate the transcriptional binding of MYC. Importantly, we found that squalene, an isoprenoid found in several herbal extracts in NE India could modulate MYC activity by an unknown mechanism. Conclusion: Our results indicate that the vast, untapped herbal plants available in India’s remote North East contain valuable herbal medicinal plant having potential MYC inhibitor. 1. Das B et al. MYC through HIF-2alpha regulates the self-renewal program in cancer stem cells (under review). Note: This abstract was not presented at the meeting. Citation Format: Sora Sandhya, Joyeeta Talukdar, Bidisha Pal, Seema Bhuyan, Debabrat Baishya, Bikul Das. Identification and characterization of Novel MYC and p53 target molecules from medicinal plants of North East India [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4020. doi:10.1158/1538-7445.AM2017-4020