Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

作者全名："Huang, Linjuan; Zhao, Ling; Zhang, Jing; He, Fang; Wang, Hao; Liu, Qing; Shi, Deyao; Ni, Na; Wagstaff, William; Chen, Connie; Reid, Russell R.; Haydon, Rex C.; Luu, Hue H.; Shen, Le; He, Tong-Chuan; Tang, Liangdan"

作者地址："[Huang, Linjuan; Zhao, Ling; Zhang, Jing; Tang, Liangdan] Chongqing Med Univ, Dept Obstet & Gynecol, Affiliated Hosp 1, Chongqing, Peoples R China; [Huang, Linjuan; Zhao, Ling; Zhang, Jing; He, Fang; Wang, Hao; Liu, Qing; Shi, Deyao; Ni, Na; Wagstaff, William; Chen, Connie; Reid, Russell R.; Haydon, Rex C.; Luu, Hue H.; Shen, Le; He, Tong-Chuan] Univ Chicago, Mol Oncol Lab, Dept Orthopaed Surg & Rehabil Med, Med Ctr, Chicago, IL 60637 USA; [He, Fang] Chongqing Med Univ, Dept Med Gastroenterol, Affiliated Hosp 1, Chongqing, Peoples R China; [Wang, Hao; Ni, Na] Chongqing Med Univ, Minist Educ, Key Lab Diagnost Med, Chongqing, Peoples R China; [Wang, Hao; Ni, Na] Chongqing Med Univ, Sch Lab Diagnost Med, Chongqing, Peoples R China; [Liu, Qing] Cent South Univ, Xiangya Hosp 2, Dept Spine Surg, Changsha 410011, Peoples R China; [Shi, Deyao] Huazhong Univ Sci & Technol, Union Hosp Tongji Med Coll, Dept Orthopaed Surg, Wuhan 430022, Peoples R China; [Reid, Russell R.] Univ Chicago, Dept Surg, Sect Plast Surg, Med Ctr, Chicago, IL 60637 USA; [Shen, Le; He, Tong-Chuan] Univ Chicago, Med Ctr, Dept Surg, Chicago, IL 60637 USA"

通信作者："Tang, LD (corresponding author), Chongqing Med Univ, Dept Obstet & Gynecol, Affiliated Hosp 1, Chongqing, Peoples R China.; He, TC (corresponding author), Univ Chicago, Mol Oncol Lab, Dept Orthopaed Surg & Rehabil Med, Med Ctr, Chicago, IL 60637 USA.; He, TC (corresponding author), Univ Chicago, Med Ctr, Dept Surg, Chicago, IL 60637 USA."

来源：AGING-US

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000681283300002

JCR分区：Q2

影响因子：5.2

年份：2021

卷号：13

期号：13

开始页：17407

结束页：17427

文献类型：Article

关键词：ovarian cancer; cisplatin; chemoresistance; cisplatin resistance; mebendazole (MBZ); drug repurposing

摘要："Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies."

基金机构：National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA226303]; Medical Scientist Training Program of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32 GM007281]; University of Chicago Cancer Center Support Grant [P30CA014599]; National Center for Advancing Translational Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR000430]; Mabel Green Myers Research Endowment Fund; University of Chicago Orthopaedics Alumni Fund; University of Chicago SHOCK Fund

基金资助正文："The reported work was supported in part by research grants from the National Institutes of Health (CA226303 to TCH) . WW was supported by the Medical Scientist Training Program of the National Institutes of Health (T32 GM007281) . This project was also supported in part by The University of Chicago Cancer Center Support Grant (P30CA014599) and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430. TCH was supported by the Mabel Green Myers Research Endowment Fund, The University of Chicago Orthopaedics Alumni Fund, and The University of Chicago SHOCK Fund. Funding sources were not involved in the study design; in the collection, analysis and/or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication."