Huang Gangxiong, Mills Lisa, Worth Laura L
Division of Pediatrics, Unit 087, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Mol Cancer Ther. 2007 May;6(5):1610-9. doi: 10.1158/1535-7163.MCT-06-0580.
Chemoresistance is a major reason that patients with osteosarcoma fail to achieve a lasting chemotherapy response, and it contributes to disease relapse, progression, and death. Human glutathione S-transferase P1 (GSTP1), a phase II detoxification enzyme, contributes to chemoresistance in many cancers. However, the role of GSTP1 in osteosarcoma chemoresistance is ill defined. We hypothesized that GSTP1 has cytoprotective effects in human osteosarcoma. To assess this possibility, we used GSTP1 cDNA transfection or RNA interference to overexpress or suppress GSTP1 in osteosarcoma cells, and assessed the cytotoxic effect of chemotherapeutic agents on these cells. Our results showed that GSTP1 expression was up-regulated in osteosarcoma cells when they were treated with doxorubicin or cisplatin. GSTP1 overexpression in SAOS-2 osteosarcoma cells caused the cells to be more resistant to doxorubicin and cisplatin. In contrast, GSTP1 suppression in HOS cells caused more apoptosis and extensive DNA damage in response to doxorubicin and cisplatin. The cytotoxicity assay also showed that GSTP1 suppression caused a 2.5-fold increase in cell growth inhibition resulting from doxorubicin and cisplatin treatments [the IC(50)s are approximately 0.16 micromol/L (doxorubicin) and 1.8 micromol/L (cisplatin) for parental HOS versus 0.06 micromol/L (doxorubicin) and 0.75 micromol/L (cisplatin) for GSTP1-silenced HOS]. Moreover, GSTP1 suppression decreased the activation of extracellular signal-regulated kinase 1/2, which is induced by cisplatin and doxorubicin. Taken together, these findings show that GSTP1 contributes to doxorubicin and cisplatin resistance in osteosarcoma, which may be mediated in part by the activation of extracellular signal-regulated kinase 1/2. Targeting of GSTP1 combined with chemotherapy may have synergistic therapeutic effects on osteosarcoma.
化疗耐药是骨肉瘤患者无法实现持久化疗反应的主要原因，它会导致疾病复发、进展和死亡。人类谷胱甘肽S-转移酶P1（GSTP1）是一种II期解毒酶，在许多癌症中都与化疗耐药有关。然而，GSTP1在骨肉瘤化疗耐药中的作用尚不明确。我们假设GSTP1在人类骨肉瘤中具有细胞保护作用。为了评估这种可能性，我们使用GSTP1 cDNA转染或RNA干扰在骨肉瘤细胞中过表达或抑制GSTP1，并评估化疗药物对这些细胞的细胞毒性作用。我们的结果表明，当骨肉瘤细胞用阿霉素或顺铂处理时，GSTP1表达上调。SAOS-2骨肉瘤细胞中GSTP1的过表达使细胞对阿霉素和顺铂更具抗性。相反，HOS细胞中GSTP1的抑制导致对阿霉素和顺铂产生更多的细胞凋亡和广泛的DNA损伤。细胞毒性试验还表明，GSTP1的抑制导致阿霉素和顺铂处理引起的细胞生长抑制增加2.5倍[亲本HOS细胞对阿霉素和顺铂的半数抑制浓度（IC50）分别约为0.16微摩尔/升和1.8微摩尔/升，而GSTP1沉默的HOS细胞对阿霉素和顺铂的IC50分别为0.06微摩尔/升和0.75微摩尔/升]。此外，GSTP1的抑制降低了由顺铂和阿霉素诱导的细胞外信号调节激酶1/2的激活。综上所述，这些发现表明GSTP1在骨肉瘤中导致对阿霉素和顺铂的耐药，这可能部分是由细胞外信号调节激酶1/2的激活介导的。靶向GSTP1联合化疗可能对骨肉瘤具有协同治疗作用。
