title: Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation.
abstract: Chemotherapy resistance represents a major problem for the treatment of patients with lung carcinomas. Parthenolide (PN), a naturally occurring small molecule found in herb feverfew, has been used in clinical treatment. Although its importance in treating the chemotherapy resistance has been shown, the pharmacological benefits of PN for lung cancer with multidrug resistance are underappreciated. Using human lung epithelial carcinoma A549 and A549 derived DOX-resistant A549/DOX cell lines, we found that PN enhanced the apoptotic cytotoxicity of DOX in A549/DOX cells. PN inhibited P-glycoprotein (P-gp) up-regulation and promoted the intracellular accumulation of DOX in A549/DOX cells. PN also exhibited inhibitory effect on NF-κB activation in A549/DOX cells, suggesting that inhibition of NF-κB was involved in attenuating P-gp expression by PN. Moreover, we found that PN could also effectively inhibit the HSP70 up-regulation in A549/DOX cells. Further studies revealed a positive correlation between HSP70 and P-gp expression. Overexpression of HSP70 upregulated P-gp expression independently of NF-κB activation in A549 cells, and knockdown of HSP70 caused a reduced expression of P-gp in A549/DOX cells. RT-PCR experiments showed that HSP70 modulated the P-gp expression mainly at transcription level. Taken together, PN can reverse DOX resistance through suppressing P-gp expression by mechanisms involving attenuation of NF-κB activation and HSP70 up-regulation. Our results not only provide insight into potential use of PN in reversing P-gp mediated MDR to facilitate lung cancer chemotherapy, but also highlight a potential role of HSP70 in the development of drug resistance.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.
authors.forename: Yinqiang
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.
authors.forename: Shimei
authors.initials: S
authors.lastname: Qi
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.
authors.forename: Yimiao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, Jiangsu, PR China. Electronic address: lanluo@nju.edu.cn.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China. Electronic address: lanlei1978@gmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Lan
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China. Electronic address: yinzhimin@njnu.edu.cn.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000378:metabolism; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D004317:Doxorubicin
keywords: Doxorubicin resistance; HSP70; NF-κB; P-glycoprotein; Parthenolide