title: Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis.
abstract: Both betulinic acid (BA) and mithramycin A (MIT) exhibit potent antitumor activity through distinct mechanisms of Sp1 inhibition. However, it is unknown whether a combination of these two compounds results in a synergistic inhibitory effect on pancreatic cancer growth and/or has a therapeutic advantage over gemcitabine. In xenograft mouse models of human pancreatic cancer, treatment with either BA or MIT alone showed dose-dependent antitumor activity but led to systemic side effects as measured by overall weight loss. Treatment with a nontoxic dose of either compound alone had only marginal antitumor effects. Importantly, combination treatment with nontoxic doses of BA and MIT produced synergistic antitumor activity, including inhibitory effects on cell proliferation, invasion, and angiogenesis. The treatment combination also produced less discernible side effects than therapeutic doses of gemcitabine. Moreover, combined treatment of BA and MIT resulted in drastic inhibition of Sp1 recruitment onto Sp1 and VEGF promoters, leading to transcriptional inhibition of both Sp1 and VEGF and downregulation of Sp1 and VEGF protein expression. Ectopic overexpression of Sp1 rendered tumor cells resistant to BA, MIT, and the combination of the two. Overall, our findings argue that Sp1 is an important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer.
authors.affiliation: Department of Oncology, Shanghai Tongji University Affiliated East Hospital, Shanghai.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Kong
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: David Z
authors.initials: DZ
authors.lastname: Chang
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Le
authors.forename: Huang
authors.initials: H
authors.lastname: Suyun
authors.forename: Shengdong
authors.initials: S
authors.lastname: Huang
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007797:Laminin; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053978:Pentacyclic Triterpenes; D008926:Plicamycin / Q000008:administration & dosage / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016329:Sp1 Transcription Factor / Q000235:genetics; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000094062:Betulinic Acid
chemical_list: D004338:Drug Combinations; D007797:Laminin; D053978:Pentacyclic Triterpenes; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D008926:Plicamycin; D000094062:Betulinic Acid