Tags

Type your tag names separated by a space and hit enter

Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation.
Toxicol Lett. 2013 Aug 14; 221(2):73-82.TL

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+Show Affiliations

Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210023, Jiangsu, PR China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, Jiangsu, PR China. Electronic address: lanluo@nju.edu.cn.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23792430

Citation

Xin, Yinqiang, et al. "Parthenolide Reverses Doxorubicin Resistance in Human Lung Carcinoma A549 Cells By Attenuating NF-κB Activation and HSP70 Up-regulation." Toxicology Letters, vol. 221, no. 2, 2013, pp. 73-82.
Xin Y, Yin F, Qi S, et al. Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation. Toxicol Lett. 2013;221(2):73-82.
Xin, Y., Yin, F., Qi, S., Shen, L., Xu, Y., Luo, L., Lan, L., & Yin, Z. (2013). Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation. Toxicology Letters, 221(2), 73-82. https://doi.org/10.1016/j.toxlet.2013.06.215
Xin Y, et al. Parthenolide Reverses Doxorubicin Resistance in Human Lung Carcinoma A549 Cells By Attenuating NF-κB Activation and HSP70 Up-regulation. Toxicol Lett. 2013 Aug 14;221(2):73-82. PubMed PMID: 23792430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parthenolide reverses doxorubicin resistance in human lung carcinoma A549 cells by attenuating NF-κB activation and HSP70 up-regulation. AU - Xin,Yinqiang, AU - Yin,Fei, AU - Qi,Shimei, AU - Shen,Lei, AU - Xu,Yimiao, AU - Luo,Lan, AU - Lan,Lei, AU - Yin,Zhimin, Y1 - 2013/06/20/ PY - 2013/02/28/received PY - 2013/06/10/revised PY - 2013/06/12/accepted PY - 2013/6/25/entrez PY - 2013/6/25/pubmed PY - 2014/12/17/medline KW - Doxorubicin resistance KW - HSP70 KW - NF-κB KW - P-glycoprotein KW - Parthenolide SP - 73 EP - 82 JF - Toxicology letters JO - Toxicol. Lett. VL - 221 IS - 2 N2 - 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/23792430/Parthenolide_reverses_doxorubicin_resistance_in_human_lung_carcinoma_A549_cells_by_attenuating_NF_κB_activation_and_HSP70_up_regulation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(13)01078-3 DB - PRIME DP - Unbound Medicine ER -