title: Arsenic trioxide-enhanced, matrine-induced apoptosis in multiple myeloma cell lines.
abstract: Matrine and arsenic trioxide are monomers used in traditional Chinese medicine possessing anti-myeloma activities. In this study, we evaluated the effects and mechanisms of matrine, arsenic trioxide, and their combination therapy on the proliferation and apoptosis of the myeloma cell lines RPMI8226 and U266. The effects of growth inhibition were measured by MTT, and apoptotic cells were analyzed by Hoechst 33258 staining and flow cytometry. The levels of caspase-3, poly (ADP-ribose) polymerase (a DNA repair enzyme), Bcl-2 and survivin (antiapoptotic signaling proteins), Bim (a proapoptotic signaling protein), total AKT, and phosphorylated AKT were evaluated by Western blot. Matrine significantly inhibited proliferation of RPMI8226 and U266 cell lines in a dose- and time-dependent manner with an IC₅₀ at 24 h of 2.25 g/L and 2.18 g/L, and at 48 h of 1.64 g/L and 1.58 g/L, respectively. Arsenic trioxide also displayed a dose- and time-dependent inhibition of growth of multiple myeloma cell lines, and synergistic effects occurred when the two were combined. Matrine (0.5, 1.0 g/L) and arsenic trioxide (2, 4 ug/mL) induced the apoptosis of myeloma cells; more early-stage apoptotic cells were seen with the combination therapy (matrine 0.5 g/L plus arsenic trioxide 2 ug/mL and matrine 1.0 g/L plus arsenic trioxide 4 ug/mL). Activation of caspase-3 and poly (ADP-ribose) polymerase, upregulation of Bim expression, downregulation of Bcl-2, survivin expression, as well as inhibition of phosphorylated AKT related to matrine (0, 0.25, 0.5, 1.0, and 2.0 g/L)-mediated apoptosis, and the effects were enhanced when arsenic trioxide (8 ug/mL) was combined with matrine (1.0 g/L). In conclusion, matrine displayed anti-myeloma effects through apoptotic induction, and arsenic trioxide had synergistic effects with matrine enhancing matrine-induced apoptosis.
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, ZheJiang, China.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Yu
authors.forename: Binhai
authors.initials: B
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: WenBin
authors.initials: W
authors.lastname: Qian
authors.forename: Baodong
authors.initials: B
authors.lastname: Ye
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008516:Medicine, Chinese Traditional / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011807:Quinolizines / Q000008:administration & dosage / Q000494:pharmacology*; D000077022:Survivin; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C000606775:BCL2L11 protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D010087:Oxides; D011518:Proto-Oncogene Proteins; D011807:Quinolizines; D000077022:Survivin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D000077237:Arsenic Trioxide; D000093842:Matrines