Abstract
Metformin has been shown to inhibit tumor growth in xenograft rodent models of adult cancers, and various human clinical trials are in progress. However, the precise molecular mechanisms of metformin action are largely unknown. In the present study we examined the anti-tumor activity of metformin against neuroblastoma, and determined the underlying signaling mechanisms. Using human neuroblastoma xenograft mice, we demonstrated that oral administration of metformin (100 and 250 mg/kg body weight) significantly inhibited the growth of tumors. The interference of metformin in spheroid formation further confirmed the anti-tumor activity of metformin. In tumors, the activation of Rac1 (GTP-Rac1) and Cdc42 (GTP-Cdc42) was increased while RhoA activation (GTP-RhoA) was decreased by metformin. It also induced phosphorylation of JNK and inhibited the phosphorylation of ERK1/2 without affecting p38 MAP Kinase. Infection of cells by adenoviruses expressing dominant negative Rac1 (Rac1-N17), Cdc42 (Cdc42-N17) or constitutively active RhoA (RhoA-V14), or incubation of cells with pharmacological inhibitors of Rac1 (NSC23766) or Cdc42 (ML141) significantly protected neuroblastoma cells from metformin-induced apoptosis. Additionally, inhibition of JNK activity along with Rac1 or Cdc42 attenuated cytotoxic effects of metformin. These studies demonstrated that metformin impairs Rho GTPases signaling to induce apoptosis via JNK pathway.
Highlights
Neuroblastoma is solid tumor of the postganglionic sympathetic nervous system, arises in the adrenal glands and spreads to various organs such as liver, bone, lymph nodes, neck and chest [1]
Using two human neuroblastoma cell lines of different genotype- SH-SY5Y (MYCN-non amplified) and SK-N-BE(2) cells (MYCNamplified, multi-drug resistant), our in vivo studies demonstrate that metformin significantly inhibits the growth of tumors in xenograft mice (Fig. 1)
Metformin reduces viability of neuroblastoma cells (Fig. 3C-D) and its interference with the spheroid formation in 3-D cultures (Fig. 3A-B) further confirms the anti-neoplastic effect of metformin against neuroblastoma. These data indicate that SK-N-BE(2) cells (MYCN-amplified and harbor p53 mutation) are more sensitive to metformin compared to SH-SY5Y cells
Summary
Neuroblastoma is solid tumor of the postganglionic sympathetic nervous system, arises in the adrenal glands and spreads to various organs such as liver, bone, lymph nodes, neck and chest [1]. It is the most common cancer in babies younger than one and second most common tumors in children. In the United States of America, approximately 700 children are diagnosed with neuroblastoma each year. It accounts for 7% of all childhood cancers (Cancer Facts & Figures 2014, Atlanta, GA: American Cancer Society), and is responsible for 15% of all cancer deaths in children younger than 15 years. Search for novel therapeutic compounds that can work on a wide range of neuroblastoma cells are desperately needed for neuroblastoma therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
