title: VEGF depletion enhances bcr-abl-specific sensitivity of arsenic trioxide in chronic myelogenous leukemia.
abstract: The development of resistance to imatinib mesylate may partly depend on high bcr-abl expression levels or point mutation(s). Arsenic trioxide (ATO) has bcr-abl suppressing activity in vitro, without cross-resistance to imatinib. Meanwhile, bcr-abl also induces expression of vascular endothelial growth factor (VEGF), which is associated with tumor-related angiogenesis and is involved in chronic myelogenous leukemia (CML) pathogenesis. Here, we investigated ways to improve ATO activity in CML by modulating cellular VEGF levels. K562 and primary CML cells were transfected with a VEGF antisense sequence. Cell viability and survival were assessed using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide and trypan blue exclusion assays. Apoptotic cells were detected by flow cytometry following annexin V and propidium iodide staining. The results showed that VEGF depletion effectively promotes enhanced ATO antileukemic activity by repressing bcr-abl protein levels. These data provide a rationale for the clinical development of optimized ATO-based regimens that incorporate VEGF modulator for CML treatment.
authors.affiliation: Medical College of Jinan University, Guangzhou, China.
authors.forename: Xiaochuang
authors.initials: X
authors.lastname: Luo
authors.forename: Maoxiao
authors.initials: M
authors.lastname: Feng
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Yumin
authors.initials: Y
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Fei
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D010087:Oxides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D001152:Arsenicals; D001549:Benzamides; D020319:Oligodeoxyribonucleotides, Antisense; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000077237:Arsenic Trioxide