Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.
Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha.
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DOI：
10.1371/journal.pone.0065304
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Makin G
中科院分区：
文献类型：
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作者：
Adamski J;Price A;Dive C;Makin G
过去 40 年来，儿童癌症的存活率显着提高，目前超过 80% 的儿童已被治愈。然而，在某些亚组中，包括转移性骨肉瘤，尽管采用了剂量密集的多药化疗方案，但生存率仍然很低，并且需要新的治疗方法。缺氧在成人实体瘤中很常见，并且与治疗抵抗和较差的结果相关。在体外，缺氧会诱导儿童肿瘤（包括神经母细胞瘤、横纹肌肉瘤和尤文氏肉瘤）对化疗产生耐药性，而这种耐药性依赖于氧调节转录因子缺氧诱导因子-1（HIF-1）。在本研究中，评估了缺氧对骨肉瘤细胞系 791T、HOS 和 U2OS 对临床相关细胞毒素顺铂、阿霉素和依托泊苷反应的影响。在所有三种细胞系中都观察到明显的缺氧诱导的对所有三种药物的耐药性，并且缺氧显着减少了药物诱导的细胞凋亡。缺氧还减弱了 p53 野生型 U2OS 骨肉瘤细胞中药物诱导的 p53 激活。氯化钴在常氧条件下稳定 HIF-1α 不会诱导耐药性，也不会因 shRNAi、siRNA、显性失活 HIF 或小分子 NSC-134754 抑制缺氧条件下 HIF-1α 的抑制而逆转耐药性，这强烈表明缺氧诱导的骨肉瘤细胞耐药性与 HIF-1α 无关。使用抑制剂 PI-103 抑制磷酸肌醇 3 激酶 (PI3K) 通路并不能逆转缺氧诱导的耐药性，表明骨肉瘤细胞中 Akt 的缺氧激活在缺氧诱导的耐药性中并未发挥重要作用。针对缺氧是改善当前抗癌治疗和对抗耐药性的令人兴奋的前景。骨肉瘤细胞中显着的缺氧诱导的耐药性凸显了缺氧作为逆转小儿骨肉瘤耐药性的目标的潜在重要性。 HIF-1α 独立耐药性的新发现表明，其他与缺氧相关的靶标可能与儿童骨肉瘤更相关。
Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing’s sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1). In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1α stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1α in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1α. Inhibition of the phosphoinositide 3-kinase (PI3K) pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target to reverse drug resistance in paediatric osteosarcoma. The novel finding of HIF-1α independent drug resistance suggests however other hypoxia related targets may be more relevant in paediatric osteosarcoma.
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影响因子：
6.4
作者：
Hao, J.;Song, X.;Yu, J.
通讯作者：
Yu, J.
影响因子：
11.2
作者：
Graziani, Irene;Eliasz, Sandra;Bocchetta, Maurizio
通讯作者：
Bocchetta, Maurizio
DOI：
10.1093/jnci/86.17.1297
发表时间：
1994-09-07
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
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作者：
FLORENES, VA;MAELANDSMO, GM;FODSTAD, O
通讯作者：
FODSTAD, O
影响因子：
5.7
作者：
Hussein, Deema;Estlin, Edward J.;Makin, Guy W. J.
通讯作者：
Makin, Guy W. J.
影响因子：
8.8
作者：
通讯作者：
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