title: Novel Benzo[a]quinolizidine Analogs Induce Cancer Cell Death through Paraptosis and Apoptosis.
abstract: Paraptosis is nonapoptotic cell death characterized by massive endoplasmic reticulum (ER)- or mitochondria-derived vacuoles. Induction of paraptosis offers significant advantages for the treatment of chemotherapy-resistant tumors compared with anticancer drugs that rely on apoptosis. Because some natural alkaloids induce paraptotic cell death, a novel series of benzo[a]quinolizidine derivatives were synthesized, and their antiproliferative activity and ability to induce cytoplasmic vacuolation were analyzed. Structural optimization led to the identification of the potent compound 22b, which inhibited cancer cell proliferation in vitro and in vivo and profoundly facilitated paraptosis-like cell death and induced caspase-dependent apoptosis. Further investigation revealed that 22b-mediated vacuolation originated from persistent ER stress and upregulation of LC3B. Paraptosis induced by benzo[a]quinolizidine derivatives thus represents an alternative strategy for cancer chemotherapy.
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, ‡Department of Biochemistry and Molecular Biology, School of Medicine, and §National Glycoengineering Research Center, Shandong University , No.44 Western Wenhua Road, Jinan 17923, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology*; D054837:Quinolizidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D054837:Quinolizidines