Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved.
Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved.
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DOI：
10.1371/journal.pone.0061524
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bhat MK
中科院分区：
文献类型：
--
作者：
Meena AS;Sharma A;Kumari R;Mohammad N;Singh SV;Bhat MK
肝细胞癌是肝脏的主要恶性肿瘤，也是世界范围内癌症相关死亡的主要原因。只有10%到20%的肝细胞癌可以通过手术切除。因此，化疗干预和治疗是获得良好预后的关键。然而，由于癌细胞对化疗的固有抵抗力或获得性抵抗力的形成，化疗的治疗效果通常较差。为了区分和描述分子事件，我们通过增加紫杉醇浓度处理细胞来培育耐药的Hep3B细胞(DRC)。我们还通过选择单细胞克隆并筛选耐药表型，开发了一种独特的Hep3B细胞单细胞克隆(SCC)。有趣的是，与亲本的Hep3B细胞相比，DRC和SCC都对紫杉醇耐药。我们分析了可能参与抗药性发展的因素。正如预期的那样，DRC患者的P-糖蛋白(P-gp)水平升高。此外，小窝蛋白-1(Cav-1)、脂肪酸合成酶(FASN)和细胞色素P450(CYP450)蛋白水平在DRC中升高，而在SCC中FASN和CYP450蛋白水平升高。通过各自的siRNA和/或特定的药物抑制剂下调这些分子，使细胞对紫杉醇重新敏感。有趣的是，除顺铂外，这些耐药细胞对长春花碱、阿霉素和甲氨蝶呤的敏感性也较低。我们的结果提示P-gp、Cav-1和FASN的不同水平在肝细胞癌的获得性耐药表型中起主要作用，而FASN的水平与固有耐药表型的出现有关。
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is a major cause of cancer related deaths worldwide. Only 10 to 20% of HCC can be surgically excised. Therefore, chemotherapeutic intervention and treatment is essential for achieving favorable prognosis. However, therapeutic outcome of chemotherapy is generally poor owing to inherent resistance of cancer cells to the treatment or due to development of acquired resistance. To differentiate and delineate the molecular events, we developed drug resistant Hep3B cells (DRC) by treating cells with the increasing concentration of paclitaxel. We also developed a unique single cell clone of Hep3B cells (SCC) by selecting single cell colonies and screening them for resistant phenotype. Interestingly, both DRC and SCC were resistant to paclitaxel in comparison to parental Hep3B cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, level of P-glycoprotein (P-gp) was elevated in DRC. In addition, Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) protein levels were elevated in DRC whereas in SCC, FASN and CYP450 levels were elevated. Downregulation of these molecules by respective siRNAs and/or by specific pharmacological inhibitors resensitized cells to paclitaxel. Interestingly, these drug resistant cells were also less sensitive to vinblastine, doxorubicin and methotrexate with the exception of cisplatin. Our results suggested that differential levels of P-gp, Cav-1 and FASN play a major role in acquired resistant phenotype whereas FASN level was associated with the presentation of inherent resistant phenotype in HCC.