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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)74-84
Number of pages11
JournalEuropean Journal of Pharmacology
Volume670
Issue number1
DOIs
Publication statusPublished - Nov 16 2011

Keywords

  • ABCB1
  • ABCG2
  • Breast cancer
  • Colon cancer
  • CPT-11
  • Doxorubicin
  • MC70
  • Topotecan

ASJC Scopus subject areas

  • Pharmacology

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