Abstract | BACKGROUND: METHODS: Resistant cell lines (H3122/DR-1, H3122/DR-2 and H2228/DR) were established by repeated exposure to increasing concentrations of 17-DMAG. Mechanisms for resistance by either NAD(P)H/ quinone oxidoreductase 1 (NQO1), previously known as a factor related to 17-DMAG resistance, or P-glycoprotein (P-gp; ABCB1/MDR1) were queried using RT-PCR, western blot analysis, chemical inhibitors, the MTT cell proliferation/survival assay, and cellular efflux of rhodamine 123. RESULTS: The resistant cells showed no cross-resistance to AUY922 or ALK inhibitors, suggesting that ALK dependency persists in cells with acquired resistance to 17-DMAG. Although expression of NQO1 was decreased in H3122/DR-1 and H3122/DR-2, NQO1 inhibition by dicumarol did not affect the response of parental cells (H2228 and H3122) to 17-DMAG. Interestingly, all resistant cells showed the induction of P-gp at the protein and RNA levels, which was associated with an increased efflux of the P-gp substrate rhodamine 123 (Rho123). Transfection with siRNA directed against P-gp or treatment with verapamil, an inhibitor of P-gp, restored the sensitivity to the drug in all cells with acquired resistance to 17-DMAG. Furthermore, we also observed that the growth-inhibitory effect of 17-DMAG was decreased in A549/PR and H460/PR cells generated to over-express P-gp by long-term exposure to paclitaxel, and these cells recovered their sensitivity to 17-DMAG through the inhibition of P-gp. CONCLUSION: P-gp over-expression is a possible mechanism of acquired resistance to 17-DMAG in cells with ALK rearrangement.
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Authors | Hee Joung Kim, Kye Young Lee, Young Whan Kim, Yun Jung Choi, Jung-Eun Lee, Chang Min Choi, In-Jeoung Baek, Jin Kyung Rho, Jae Cheol Lee |
Journal | BMC cancer
(BMC Cancer)
Vol. 15
Pg. 553
(Jul 29 2015)
ISSN: 1471-2407 [Electronic] England |
PMID | 26219569
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABCB1 protein, human
- ATP Binding Cassette Transporter, Subfamily B
- Benzoquinones
- Lactams, Macrocyclic
- 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
- Dicumarol
- NAD(P)H Dehydrogenase (Quinone)
- NQO1 protein, human
- ALK protein, human
- Anaplastic Lymphoma Kinase
- Receptor Protein-Tyrosine Kinases
- Paclitaxel
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
(genetics, metabolism)
- Anaplastic Lymphoma Kinase
- Benzoquinones
(pharmacology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Dicumarol
(pharmacology)
- Drug Resistance, Neoplasm
(drug effects)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Lactams, Macrocyclic
(pharmacology)
- Lung Neoplasms
(genetics, metabolism)
- NAD(P)H Dehydrogenase (Quinone)
(genetics, metabolism)
- Paclitaxel
(pharmacology)
- Receptor Protein-Tyrosine Kinases
(genetics)
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