Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1alpha.
Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1alpha.
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DOI：
10.1007/s00280-009-1238-8
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发表时间：
2010-10
影响因子：
3
通讯作者：
Rustum, Youcef M.
中科院分区：
文献类型：
--
作者：
Chintala, Sreenivasulu;Toth, Karoly;Cao, Shousong;Durrani, Farukh A.;Vaughan, Mary M.;Jensen, Randy L.;Rustum, Youcef M.
过表达低氧诱导因子1 α（HIF-1α）的低氧肿瘤细胞通常对化疗/放疗具有抵抗性。我们已经报道了Se-甲基硒代半胱氨酸（MSC）在治疗上增强了伊立替康对人肿瘤异种移植物的疗效和选择性。本研究的目的是描述靶向HIF-1α及其转录调控基因VEGF和CAIX的观察到的疗效的机制。我们通过转染HIF-1α短发夹状RNA（shorthairpin RNA，shRNA）诱导HIF-1α稳定敲低（KD）的人头颈部鳞状细胞癌FaDu，研究MSC抑制HIF-1α的机制及其在治疗结果中的关键作用。虽然不能在体外证实甲基硒酸（MSA）与SN-38（MSC和伊立替康的活性代谢物）组合对常氧肿瘤细胞的细胞毒性功效，但低氧肿瘤细胞对该组合更敏感。通过MSA或shRNA敲低降低HIF-1α导致SN 38体外对缺氧肿瘤细胞的细胞毒性显著增加，但对常氧肿瘤细胞无影响。同样，在体内，MSC联合伊立替康治疗亲代异种移植物或伊立替康单独治疗HIF-1α KD肿瘤导致相当的治疗反应，并增加了携带FaDu异种移植物的小鼠的长期生存期。我们的研究结果表明，HIF-1α是MSC的关键靶点，其抑制与伊立替康的抗肿瘤活性增强有关。HIF-1α的抑制似乎是通过MSC稳定PHD 2、3和下调ROS介导的。因此，我们的研究结果支持MSC作为HIF-1α抑制剂在联合化疗中的发展。
Hypoxic tumor cells overexpressing hypoxia-inducible factor 1alpha (HIF-1α) are generally resistant to chemo/radiotherapy. We have reported that Se-methylselenocysteine (MSC) therapeutically enhances the efficacy and selectivity of irinotecan against human tumor xenografts. The aim of this study was to delineate the mechanism responsible for the observed efficacy targeting on HIF-1α and its transcriptionally regulated genes VEGF and CAIX. We investigated the mechanism of HIF-1α inhibition by MSC and its critical role in the therapeutic outcome by generating HIF-1α stable knockdown (KD) human head and neck squamous cell carcinoma, FaDu by transfecting HIF-1α short hairpin RNA. While cytotoxic efficacy in combination with methylselenic acid (MSA) with SN-38 (active metabolites of MSC and irinotecan) could not be confirmed in vitro against normoxic tumor cells, the hypoxic tumor cells were more sensitive to the combination. Reduction in HIF-1α either by MSA or shRNA knockdown resulted in significant increase in cytotoxicity of SN38 in vitro against hypoxic, but not the normoxic tumor cells. Similarly, in vivo, either MSC in combination with irinotecan treatment of parental xenografts or HIF-1α KD tumors treated with irinotecan alone resulted in comparable therapeutic response and increase in the long-term survival of mice bearing FaDu xenografts. Our results show that HIF-1α is a critical target for MSC and its inhibition was associated with enhanced antitumor activity of irinotecan. Inhibition of HIF-1α appeared to be mediated through stabilization of PHD2, 3 and downregulation of ROS by MSC. Thus, our findings support the development of MSC as a HIF-1α inhibitor in combination chemotherapy.
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影响因子：
11.5
作者：
Bhattacharya, A;T贸th, K;Rustum, YM
通讯作者：
Rustum, YM
影响因子：
6.4
作者：
Mizuno, T;Nagao, M;Nakajima, Y
通讯作者：
Nakajima, Y
DOI：
10.1073/pnas.0812801106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Lee, KangAe;Qian, David Z.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
3.6
作者：
Brown, LM;Cowen, RL;Williams, KJ
通讯作者：
Williams, KJ
影响因子：
7.4
作者：
Callapina, M;Zhou, J;Brüne, B
通讯作者：
Brüne, B