A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts
A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts
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DOI：
10.2174/187152012802650264
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发表时间：
2012-09-01
影响因子：
2.8
通讯作者：
Honma, Yoshio
中科院分区：
文献类型：
--
作者：
Kawakami, Koshi;Hattori, Miho;Honma, Yoshio
实体瘤中的恶性细胞在长时间缺氧下存活，并且可以成为对当前癌症疗法的抗性的来源。肿瘤缺氧还与癌症患者中更恶性的表型和较差的存活率相关。最近，我们对缺氧条件下肿瘤细胞生物学的了解取得了进展，这使得人们越来越关注针对缺氧的癌症治疗。我们在这里报告，一种新的fusicoccin衍生物（ISIR-042），但不是它的母体或相关化合物，如fusicoccin A和cotylenin A，是缺氧细胞比常氧细胞的细胞毒性。通过用ISIR-042处理，缺氧诱导的缺氧诱导因子（HIF）-1 α的积累和Akt的磷酸化被有效地抑制，这表明对缺氧细胞的优先细胞毒性与HIF-1 α和Akt活化的减少相关。ISIR-042抑制人胰腺癌MIAPaCa-2细胞的生长，同时保留正常内皮细胞，并显著抑制MIAPaCa-2细胞作为异种移植物的生长，而没有明显的不良反应。表达CD 24和CD 44的胰腺癌细胞具有干细胞的特征。用吉西他滨治疗增加了这种干细胞富集的群体，并且这种作用被ISIR-042显著抑制，表明与化疗剂相比，ISIR-042优先抑制胰腺癌细胞系中的干细胞/祖细胞。这些结果表明，ISIR-042可能是一个潜在的治疗剂缺氧肿瘤，如胰腺癌。
Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1 alpha and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1 alpha and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR-042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.