Calvin Tebbe

Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure–Activity Relationship Study

Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents.

Abstract B77: Targeting ovarian cancer promoting effects of adipocytes by metformin

At the time of surgery, 80% of the ovarian cancers are found to be metastasized to the omentum, a large fat pad covering the abdominal organs. Omental metastasis is thought to be due to the promotion of homing, growth and migration of ovarian cancer cells by factors secreted by adipocytes, which include cytokines, adipokines and growth factors. These adipocytes also act as fuel depot providing for the energy needs of fast growing ovarian tumor cells. The objective of our study was to investigate if metformin can modulate or limit the adipocyte mediated tumor-promoting and migrating effects. For this, mouse preadipocyte cells were differentiated in the presence or absence of metformin and various parameters including lipid accumulation, AMPK activation and adipogenesis transcription factors were examined. Conditioned media from undifferentiated and differentiated adipocytes was used to evaluate ID-8 mouse ovarian cancer cell proliferation and migration. Conditioned media from differentiated but not from undifferentiated preadipocytes, increased ID-8 cell proliferation (p<0.05) and migration (p<0.050), which were attenuated in presence of metformin (p<0.05). Metformin treatment inhibited adipogenesis as evident by the reduction of neutral lipid accumulation. Metformin treatment increased AMP-activated protein kinase (AMPK) activity as evident from higher level of phosphorylation of AMPK and its immediate downstream target ACC (Acetyl Co Carboxylase). It also inhibited the key adipogenesis transcription factors (CEBPαa; CEBPβb, SREBP1) during the process of adipocyte diffrenetiation. A targeted Cancer Pathway Finder RT-PCR based gene array (Qiagen) revealed 21 genes that were upreguated and 2 were downregulated more than 2-fold in ID-8 cells in presence of adipocyte conditioned media, which were modulated by metformin. Together, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation and migration. It also blunted the expression of cancer associated genes that were induced by adipocyte influence in cancer cells. This study suggests that metformin could be a therapeutic option for ovarian cancer as it not only targets ovarian cancer but alternatively, also modulates the environmental milieu around it. Citation Format: Ramandeep Rattan, Calvin Tebbe, Jasdeep Chhina, Kalli Sarigiannis, Shailendra Giri, Adnan Munkarah. Targeting ovarian cancer promoting effects of adipocytes by metformin. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B77.