Leslie C Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute and Mercy University Hospital, University College Cork, Cork, Ireland.
Br J Cancer. 2012 Feb 14;106(4):711-8. doi: 10.1038/bjc.2011.604. Epub 2012 Jan 12.
Resistance to chemotherapeutic agents has been associated with a failure of cancer cells to induce apoptosis. Strategies to restore apoptosis have led to the development of BH3 mimetics, which inhibit anti-apoptotic Bcl-2 family members. We examined the sensitivity of three oesophageal cancer cell lines to 5-fluorouracil (5-FU) alone and in combination with the BH3 mimetic HA14-1.
Clonogenic assays, morphology, markers of autophagy and apoptosis were used to assess the involved death mechanisms.
In response to 5-FU treatment, OE21 cells induce apoptosis, KYSE450 and KYSE70 cells are more resistant and induce autophagy accompanied by type II cell death. Autophagy induction results in ineffective treatment as substantial numbers of cells survive and re-populate. HA14-1 did not improve 5-FU treatment or reduce colony re-growth in the apoptosis deficient KYSE70 cells. However, the sensitivity of OE21 (apoptotic) and KYSE450 cells (apoptosis deficient/type II cell death) was significantly improved. In OE21 cells, treatment with 5-FU and HA14-1 resulted in augmentation of apoptosis. In KYSE450 cells, the reduction in recovering colonies following combination treatment was due to the enhancement of type II cell death.
The efficacy of HA14-1 is cell line dependent and is not reliant on apoptosis induction.
癌细胞对化疗药物的耐药性与细胞无法诱导细胞凋亡有关。为了恢复细胞凋亡，人们开发了 BH3 模拟物，它可以抑制抗凋亡的 Bcl-2 家族成员。我们研究了三种食管癌细胞系对氟尿嘧啶（5-FU）单独用药和与 BH3 模拟物 HA14-1 联合用药的敏感性。
集落形成实验、形态学、自噬和凋亡标志物用于评估涉及的死亡机制。
OE21 细胞在接受 5-FU 治疗后会诱导细胞凋亡，KYSE450 和 KYSE70 细胞则更具耐药性，会诱导自噬并伴有 II 型细胞死亡。自噬的诱导导致治疗无效，因为大量细胞存活并重新增殖。HA14-1 不能改善 5-FU 治疗或减少凋亡缺陷的 KYSE70 细胞的集落再生长。然而，OE21（凋亡）和 KYSE450 细胞（凋亡缺陷/II 型细胞死亡）的敏感性显著提高。在 OE21 细胞中，用 5-FU 和 HA14-1 联合治疗会增强细胞凋亡。在 KYSE450 细胞中，联合治疗后恢复集落的减少是由于 II 型细胞死亡的增强。
HA14-1 的疗效依赖于细胞系，不依赖于细胞凋亡的诱导。
