Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line

collateral sensitivity to azidothymidine.

Niramol Savaraj, Chunjing Wu, Medhi Wangpaichitr, Macus Tien Kuo, Theodore Lampidis, Carlos Robles, A. J. Furst, Lynn G Feun

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cisplatin (CDDP) resistance is one of the major impediments in cancer chemotherapy. In an attempt to define this complex mechanism(s) of resistance, we have identified 7 cDNA fragments which are overexpressed in CDDP resistant small cell lung cancer cell line (SR-2) using PCR selected cDNA subtraction. One of these fragments was identical with nucleotide 3657-4042 of MRP4. The other fragments share sequence homology with elongation factor alpha, human placenta villi cDNA, heat shock protein (Hsp70), ribosomal RNA, BNP1 brain specific Na-dependent inorganic phosphate cotransporter and telomeric catalytic subunit. Examination of other MRP members (MRP1, 2, 3, 5, 6) did not show discernable differences in their expression between the parental (SCLC1) and the CDDP-resistant variant (SR-2). Full length MRP4 cDNA was obtained from SCLC1 and SR-2. Both cell lines carry a point mutation at nucleotide 3532 while SR-2 carries two additional mutations at 3228 and 3246. Since MRP4 is known to transport azidiothymidine (AZT) and overexpression of MRP4 confers AZT resistance, we have studied growth inhibitory effects of AZT and [3H]-AZT accumulation. Interestingly, SR-2 is more sensitive to AZT while accumulating lesser amounts of [3H]-AZT. The thymidine kinase activity is similar in both cell lines. Thus, the increased sensitivity to AZT in SR-2 could not be solely due to mutation of MRP4. These findings are most likely due to the inhibitory effects of telomere catalytic subunit by AZT. Thus, certain biochemical changes induced by CDDP can be explored for future treatment to overcome this form of resistance.

Original languageEnglish
Pages (from-to)173-179
Number of pages7
JournalInternational Journal of Oncology
Volume23
Issue number1
StatePublished - Jul 1 2003

Fingerprint

Zidovudine
Small Cell Lung Carcinoma
Cisplatin
Complementary DNA
Cell Line
Catalytic Domain
Vesicular Glutamate Transport Protein 1
Nucleotides
Peptide Elongation Factors
Mutation
Ribosomal RNA
Thymidine Kinase
Telomere
Sequence Homology
Heat-Shock Proteins
Point Mutation
Placenta
Drug Therapy
Polymerase Chain Reaction
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line : collateral sensitivity to azidothymidine. / Savaraj, Niramol; Wu, Chunjing; Wangpaichitr, Medhi; Kuo, Macus Tien; Lampidis, Theodore; Robles, Carlos; Furst, A. J.; Feun, Lynn G.

In: International Journal of Oncology, Vol. 23, No. 1, 01.07.2003, p. 173-179.

Research output: Contribution to journalArticle

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