title: Combination of chloroquine and GX15-070 (obatoclax) results in synergistic cytotoxicity against pancreatic cancer cells.
abstract: Pancreatic cancer is an aggressive disease with a poor prognosis. Therefore, new treatment is urgently required. GX15-070 is a pan-Bcl-2 inhibitor which has shown promising antitumor activity in different malignancies. We previously demonstrated that clinically achievable concentrations of GX15-070 caused growth arrest in pancreatic cancer cell lines. However, they only induced minimal levels of apoptosis. We hypothesized that GX15-070 induced autophagy in pancreatic cancer cells which blocked apoptosis. In this study, we investigated the effects of GX15-070 on autophagy and the antitumor activities of the combination of GX15-070 and chloroquine (CQ), an autophagy inhibitor, in six pancreatic cancer cell lines. We found that GX15-070 treatment indeed induced autophagy in 5 of the 6 pancreatic cancer cell lines, reflected by the conversion of LC3B-I to LC3B-II and detection of autophagosomes by transmission electron microscopy. Furthermore, we found additive to synergistic antitumor interactions in all six cell lines by MTT assays. CQ significantly enhanced GX15-070-induced apoptosis in the cell line models, possibly due to downregulation of Bcl-2, Bcl-xL and Mcl-1 in the cells by the two agents. These results provide compelling evidence for the further development of the combination of GX15-070 and CQ in pancreatic cancer.
authors.affiliation: National Engineering Laboratory of AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory of AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, P.R. China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Cui
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Cui
authors.affiliation: National Engineering Laboratory of AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011758:Pyrroles / Q000008:administration & dosage*; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494811:BCL2L1 protein, human; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D051020:bcl-X Protein; D002738:Chloroquine; C520962:obatoclax