开发出可抵御脑癌和乳腺癌的新型化合物

  来自夏威夷大学癌症研究中心的研究人员近日通过研究发现了两种化合物可以有效阻断脑癌细胞及乳腺癌细胞的生长，这或为开发新型潜在的癌症药物提供了新的思路，相关研究已发表在国际杂志Cancer Research上。
  研究者James Turkson说道，我们的研究成果对于脑瘤患者非常重要，因为目前除了手术外并没有有效的疗法来治疗脑瘤患者，而靶向性的疗法伤害及毒性较小，当这两种化合物被开发成为药物后，其就可以给癌症患者更好的生活质量。每年在美国大约有15，320位患者因脑癌死亡，而乳腺癌是美国女性最常见的癌症，每年因乳腺癌死亡的个体大约为40，931个。
  这项研究中，研究人员检测了化合物对蛋白质Stat3的抑制作用，Stat3是一种参与多种癌症发生的关键蛋白；这两种化合物：基于异羟肟酸的抑制剂（SH5-07）和基于苯甲酸的抑制剂（SH5-54）可以通过阻断蛋白质Stat3的特殊功能来阻断脑癌和乳腺癌细胞的生长。研究者表示，Stat3蛋白可以调节基因的表达，当其“失控”且不再发挥正常功能时，该蛋白就会驱动细胞不断生长，从而就会促进肿瘤细胞扩散，而SH5-07和SH5-54两种化合物则可以有效阻断Stat3促进癌细胞生长，最终抑制癌症恶化。
  最后研究者表示，基于本文的研究结果，后期我们还将通过更为深入的研究来开发新型疗法或药物来有效阻断致癌途径发挥作用，我们希望在后期可以将上述两种化合物改造成为新型的抗癌药物来帮助癌症患者提高生活质量及机体健康。（转化医学网360zhyx.com）
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Hydroxamic acid and benzoic acid-based Stat3 inhibitors suppress human glioma and breast cancer phenotypes in vitro and in vivo.
Cancer Res       doi:10.1158/0008-5472.CAN-14-3558
Yue P1, Lopez-Tapia F1, Paladino D1, Li Y2, Chen CH2, Hilliard T1, Chen Y2, Tius MA3, Turkson J4.STAT3 offers an attractive target for cancer therapy but small molecule inhibitors with appealing pharmacologic properties have been elusive. Here we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, Cyclin D1, c-Myc and Survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3 inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA binding activities, STAT3-independent gene transcription or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates for further development as cancer therapeutics.