Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics.

Abstract

Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.

• Authors: Christina L Grek, Zhi Sheng, Christian C Naus, Wun Chey Sin, Robert G Gourdie, Gautam G Ghatnekar
• Journal: Current opinion in pharmacology (Curr Opin Pharmacol) Vol. 41 Pg. 79-88 (08 2018) ISSN: 1471-4973 [Electronic] England
• PMID: 29803991 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• Connexin 43
• Peptidomimetics
• Temozolomide

Topics

• Antineoplastic Agents, Alkylating (therapeutic use)
• Central Nervous System Neoplasms (drug therapy)
• Connexin 43 (metabolism, physiology)
• Drug Resistance, Neoplasm
• Glioblastoma (drug therapy)
• Glioma (drug therapy)
• Humans
• Molecular Targeted Therapy
• Peptidomimetics (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Temozolomide (therapeutic use)
• Tumor Microenvironment