MC70 potentiates doxorubicin efficacy in colon and breast cancer in vitro treatment.

Abstract

A major limitation of cancer treatment is the ability of cancer cells to develop resistance to chemotherapeutic drugs, by the establishment of multidrug resistance. Here, we characterize MC70 as ABC transporters inhibitor and anticancer agent, alone or with chemotherapy. MC70 was analyzed for its interaction with ABCB1, ABCG2 and ABCC1 by specific transport assays. In breast and colon cancer cell lines, cell growth and apoptosis were measured by MTT assay and DNA laddering Elisa kit, respectively. Cell cycle perturbation and cellular targets modulation were analyzed by Flow-cytometry and Western blotting, respectively. MC70 interacted with ABC transporters. In breast cancer cells, MC70 slightly inhibited cell proliferation strongly enhancing doxorubicin effectiveness. By contrast, MC70 was found to inhibit cell growth in colon cancer cells without affecting doxorubicin efficacy and in combination with topoisomerase I inhibitors it could be a promising therapeutic approach. What is more, it was also observed that MC70 induced apoptosis, canceled in favor of necrosis when given in combination with high doses of doxorubicin. MC70 inhibited cell migration probably through its interaction with sigma-1 receptor. Modulations of i) cell cycle, ii) pAkt and the phosphorylation of the three MAPKs were highlighted, while any activity was excluded at transcription level, thus accounting for the phenotypic effects observed. MC70 might be considered as a new potential anticancer agent capable to i) enhance chemotherapy effectiveness and ii) to play a contributory role in the treatment of chemotherapy resistant tumors.

• Authors: Amalia Azzariti, Anna E Quatrale, Letizia Porcelli, Nicola A Colabufo, Mariangela Cantore, Giuseppe Cassano, Giuseppe Gasparre, Giuseppina Iannelli, Stefania Tommasi, Maria A Panaro, Angelo Paradiso
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 670 Issue 1 Pg. 74-84 (Nov 16 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21925160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• 4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Biphenyl Compounds
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Tetrahydroisoquinolines
• Irinotecan
• Topotecan
• Doxorubicin
• Camptothecin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacology)
• Breast Neoplasms (pathology)
• Camptothecin (analogs & derivatives, pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (pathology)
• Doxorubicin (pharmacology)
• Drug Synergism
• Female
• Genomics
• Humans
• Irinotecan
• Kinetics
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
• Necrosis (chemically induced)
• Neoplasm Proteins (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Tetrahydroisoquinolines (pharmacology)
• Topotecan (pharmacology)