title: Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis.
abstract: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.
authors.affiliation: Ilsong Institute for Life Science, Hallym University, Anyang 431-060, Republic of Korea.
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Park
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Joo-Oh
authors.initials: JO
authors.lastname: Kim
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Shin
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Kim
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jo
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Lee
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
keywords: Cell death; H1299 cells; Nemadipine-A; Sensitization; TRAIL