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01-08-2007 | PRECLINICAL STUDIES

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

Authors: Gene L. Bidwell III, Aisha N. Davis, Izabela Fokt, Waldemar Priebe, Drazen Raucher

Published in: Investigational New Drugs | Issue 4/2007

Summary

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.

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Title: A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance
Authors: Gene L. Bidwell III
Aisha N. Davis
Izabela Fokt
Waldemar Priebe
Drazen Raucher
Publication date: 01-08-2007
Publisher: Kluwer Academic Publishers-Plenum Publishers
Published in: Investigational New Drugs / Issue 4/2007
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-007-9053-8

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