title: N-methylhemeanthidine chloride, a novel Amaryllidaceae alkaloid, inhibits pancreatic cancer cell proliferation via down-regulating AKT activation.
abstract: We previously reported the isolation of a novel Amaryllidaceae alkaloid, N-methylhemeanthidine chloride (NMHC), from Zephyranthes candida, which exhibits potent cytotoxicity in a spectrum of tumor cells. However, the mechanism of action remains unclear. Using multiple cell lines derived from human pancreatic cancer, one of the most mortal and refractory human malignancies, we further studied the NMHC-mediated cytotoxicity and found that it induced drastic cytotoxicity in pancreatic cancer cells whereas an insignificant effect on a noncancerous cell line. The NMHC-mediated growth inhibition was more severe than the first-line chemotherapeutic agent gemcitabine, leading to cell cycle arrest, apoptotic death and decreased glycolysis. NMHC exerted its function through down-regulating AKT activation, and the ectopic expression of activated AKT rescued the growth inhibition. Consistently, NMHC injections in a pancreatic cancer xenograft model manifested the anti-tumor effect in vivo. Engrafted tumor cells underwent AKT attenuation and apoptotic death upon treatments. As such, we here demonstrate the AKT inhibition may be one of the mechanisms by which NMHC decreases tumor cell survival rate in vitro and in vivo. Our data thereby suggest that NMHC holds great promise as a potent chemotherapeutic agent against pancreatic cancer and sheds new light on obtaining such agents from natural products toward therapeutic purposes.
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Guoli
authors.initials: G
authors.lastname: Guo
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Guangmin
authors.initials: G
authors.lastname: Yao
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Zhan
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yue
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Qing
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China. Electronic address: zhangyh@mails.tjmu.edu.cn.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei PR China. Electronic address: hudanliu@hust.edu.cn.
authors.forename: Hudan
authors.initials: H
authors.lastname: Liu
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D019668:Liliaceae / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047151:Amaryllidaceae Alkaloids; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Cell cycle; Glucose metabolism; N-methylhemeanthidine chloride; Pancreatic cancer