title: Nanosecond Pulsed Electric Fields Enhance the Anti-tumour Effects of the mTOR Inhibitor Everolimus against Melanoma.
abstract: The PI3K/mTOR/AKT pathway is activated in most melanomas, but mTOR inhibitors used singly have limited activity against advanced melanomas. The application of nanosecond pulsed electric fields (nsPEFs) is a promising cancer therapy approach. In this study, we evaluated the synergistic anti-tumour efficacy of the mTOR inhibitor everolimus in conjunction with nsPEFs against melanoma. The combined treatment of nsPEFs and everolimus gradually decreased cell growth concurrent with nsPEF intensity. nsPEFs alone or combined with everolimus could promote melanoma cell apoptosis, accompanied with a loss in cellular mitochondrial membrane potential and an increase in Ca2+levels. In vivo experiments showed that a combination of the mTOR inhibitor everolimus and nsPEFs improved the inhibitory effect, and all skin lesions caused by nsPEFs healed in 1 week without any observed adverse effect. Combination treatment induced caspase-dependent apoptosis through the upregulation of the pro-apoptotic factor Bax and downregulation of the anti-apoptotic factor Bcl-2. Everolimus and nsPEFs synergistically inhibited angiogenesis by decreasing the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and CD34. Our findings indicate that nsPEFs in combination with an mTOR inhibitor can be used as a potential treatment approach for advanced melanoma.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dai
authors.affiliation: College of Engineering, Peking University, Beijing, 100871, China.|Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Si
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Xinan
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Chuanliang
authors.initials: C
authors.lastname: Cui
authors.affiliation: College of Engineering, Peking University, Beijing, 100871, China.|Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: College of Engineering, Peking University, Beijing, 100871, China.|Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004599:Electric Stimulation Therapy / Q000379:methods*; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000150:complications / Q000628:therapy*; D008546:Melanoma, Experimental / Q000150:complications / Q000628:therapy; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000150:complications; D012878:Skin Neoplasms / Q000628:therapy*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases