Abstract
Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / adverse effects*
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Curcumin / adverse effects
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Doxorubicin / adverse effects
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Doxorubicin / pharmacokinetics
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Drug Resistance, Multiple*
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Drug Resistance, Neoplasm*
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Etoposide / adverse effects
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Glutathione Transferase / metabolism
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism*
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Paclitaxel / adverse effects
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Rhodamines / metabolism
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Tumor Cells, Cultured
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Verapamil / adverse effects
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Vinblastine / adverse effects
Substances
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Antineoplastic Agents
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Multidrug Resistance-Associated Proteins
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RNA, Messenger
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RNA, Neoplasm
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Rhodamines
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lissamine rhodamine B
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Vinblastine
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Etoposide
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Doxorubicin
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Verapamil
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Glutathione Transferase
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Curcumin
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Paclitaxel