Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin
Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin
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DOI：
10.1038/sj.leu.2401856
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发表时间：
2000-08-01
期刊：
影响因子：
11.4
通讯作者：
Ohno, R
中科院分区：
文献类型：
--
作者：
Maksumova, L;Ohnishi, K;Ohno, R
洛伐他汀是一种HMG-CoA还原酶的竞争性抑制剂，据报道可抑制MDR-1编码的P-糖蛋白（Pgp）表达的肿瘤细胞的增殖并诱导其凋亡。本研究观察了8种髓系白血病细胞系K562、NOMO-1、NB 4及其维甲酸（RA）耐药亚系NB 4/RA，以及它们的多药耐药亚系K562/ADR、NOMO-1/ADR、NB 4/MDR和NB 4/RA/MDR对洛伐他汀的敏感性。MTT法和细胞凋亡实验表明，K562/ADR、NOMO-1/ADR和NB 4/RA/MDR细胞对洛伐他汀的敏感性高于其亲本细胞，而NB 4/MDR细胞对洛伐他汀的敏感性与亲本细胞NB 4相当。通过半定量RT-PCR分析，观察到HMG-CoA还原酶的转录水平显着升高，在超过三个洛伐他汀敏感的MDR亚系，但没有在NB 4/MDR与亲本细胞系相比。在所有亲本非Pgp表达细胞系中，洛伐他汀暴露使HMG-CoA还原酶mRNA水平上调2倍以上。在NB 4/MDR中，HMG-CoA还原酶mRNA水平升高到与亲本NB 4相似的程度，而在其他三个对洛伐他汀优先敏感的MDR亚系中，其HMG-CoA还原酶mRNA水平在用洛伐他汀处理24和48小时后没有显著升高。这些结果表明耐药性和甲羟戊酸途径的调节之间的联系，并进一步加强了临床可能性，耐药性白血病将易受洛伐他汀治疗。
Lovastatin, a competitive inhibitor of HMG-CoA reductase, reportedly inhibits proliferation and induces apoptosis of tumor cells with MDR-1 coded P-glycoprotein (Pgp) expression. In this study we investigated the sensitivity to lovastatin of eight myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic acid (RA) resistant subline NB4/RA, and their multidrug-resistant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and NB4/RA/MDR. MTT and apoptosis assays revealed that K562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive to lovastatin than their parental cell lines, while NB4/MDR showed the same level of sensitivity as parental NB4 cells, which already were very sensitive to lovastatin. Significant elevation of transcript levels of HMG-CoA reductase was observed by semiquantitative RT-PCR analysis in more than three lovastatin-sensitive MDR sublines, but not in NB4/MDR compared with the parental cell lines. HMG-CoA reductase mRNA levels were up-regulated more than two-fold by the exposure to lovastatin in all of the parental non-Pgp-expressing cell lines. In NB4/MDR, HMG-CoA reductase mRNA level was elevated to a similar extent as in parental NB4, whereas in three other MDR sublines which showed preferential sensitivity to lovastatin, their HMG-CoA reductase mRNA levels were not significantly elevated after 24- and 48-h treatment with lovastatin. These results indicate a connection between drug resistance and regulation of the mevalonate pathway, and further strengthen the clinical possibility that drug resistant leukemias would be susceptible to treatment with lovastatin.