Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
Cancer Lett. 2015 Aug 10;364(2):156-64. doi: 10.1016/j.canlet.2015.05.008. Epub 2015 May 12.
Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1α-stabilizing conditions; its possible effect on HIF-1α expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1α protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1α synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX.
缺氧诱导因子 (HIF)-1 的激活是缺氧实体肿瘤的一个特征，与耐药性有关，主要是由于 Bcl-2 家族动力学的破坏。重置有利于促凋亡家族成员的平衡是一种有吸引力的治疗目标，通过开发 BH3 模拟化合物来实现。在本研究中，我们评估了 BH3 模拟物 obatoclax (OBX) 在存在或不存在 HIF-1α 稳定条件下对人结肠腺癌细胞的生长抑制、凋亡和自噬的反应，其对 HIF-1α 表达和 HIF-1 活性的可能影响，以及通过与 OBX 联合使用来提高结肠癌细胞对细胞毒化疗药物的反应的可能性。BH3 模拟物对结肠癌细胞的反应不受 HIF-1 激活的影响，OBX 诱导 HIF-1α 蛋白水平和 HIF-1 转录活性降低，可能是通过降低 HIF-1α 的合成并促进 VHL 非依赖性蛋白酶体降解途径。最后，观察到 OBX 对 5-氟尿嘧啶或奥沙利铂治疗的化学增敏作用，突出了患有缺氧结肠肿瘤的患者可能受益于包括 OBX 在内的联合治疗方案的可能性。
