title: 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.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute Giovanni Paolo II, Bari, Italy. a.azzariti@oncologico.bari.it
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Anna E
authors.initials: AE
authors.lastname: Quatrale
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cassano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Iannelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.forename: Maria A
authors.initials: MA
authors.lastname: Panaro
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D023281:Genomics; D006801:Humans; D000077146:Irinotecan; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D009336:Necrosis / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D002166:Camptothecin; D004317:Doxorubicin; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; D019772:Topotecan; C569748:4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1