title: Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.
abstract: Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.
authors.affiliation: Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China.|Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.|Key Laboratory of Ecology and Environmental Science in Guangdong Higher Education, Guangdong Provincial Key Laboratory for Healthy and Safe Aquaculture, College of Life Science, South China Normal University, Guangzhou, 510631, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.|Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan Province, 450000, China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
authors.forename: Qipan
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan Province, 450000, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, Henan Province, 450000, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China. 2660424632@qq.com.
authors.forename: Linlin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. liy2@ccf.org.
authors.forename: Yong
authors.identifier: http://orcid.org/0000-0001-8838-1714
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D051379:Mice; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D000069286:Bortezomib; D020169:Caspases; D002955:Leucovorin