Microtubule inhibitor, SP-6-27 inhibits angiogenesis and induces apoptosis in ovarian cancer cells.
Microtubule inhibitor, SP-6-27 inhibits angiogenesis and induces apoptosis in ovarian cancer cells.
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DOI：
10.18632/oncotarget.17549
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Beaman KD
中科院分区：
文献类型：
--
作者：
Kulshrestha A;Katara GK;Ibrahim SA;Patil R;Patil SA;Beaman KD
在卵巢癌（OVCA）中，由于化疗耐药性导致的治疗失败是一个严重的挑战。因此，确定有效对抗耐药肿瘤并减少副作用的新疗法至关重要。我们最近发现4-H-色烯作为微管蛋白解聚剂，结合到β-微管蛋白的秋水仙碱位点。在这里，我们筛选了取代的4-H-色烯的化学文库，并鉴定了SP-6-27对一组人顺铂敏感和耐药OVCA细胞系表现出最有效的抗增殖活性，50%抑制浓度（IC 50;平均值± SD）范围为0.10 ± 0.01至0.84 ± 0.20 μM。SP-6-27对正常卵巢上皮细胞的细胞毒性最小。在SP-6-27处理的顺铂敏感/耐药OVCA细胞中观察到微管密度的显著降低以及G2/M细胞周期阻滞。SP-6-27诱导细胞死亡的分子机制揭示了通过上调生长停滞和DNA损伤诱导的α转录物（GADD 45）来调节细胞周期调节。通过上调Bax、Apaf-1、caspase-6、-9和caspase-3，在OVCA细胞中观察到增强的内在凋亡。体外伤口愈合测定显示SP-6-27处理后OVCA细胞迁移减少。此外，SP-6-27和顺铂组合处理在化学敏感/抗性OVCA细胞中显示出增强的细胞毒性。SP-6-27除了对癌细胞的作用外，还通过抑制人脐静脉内皮细胞（HUVEC）的毛细血管形成来进一步抑制血管生成。总之，这些发现表明，色烯类似物SP-6-27是一种新的化疗药物，为卵巢癌的治疗提供了重要的优势。
In ovarian cancer (OVCA), treatment failure due to chemo-resistance is a serious challenge. It is therefore critical to identify new therapies that are effective against resistant tumors and have reduced side effects. We recently identified 4-H-chromenes as tubulin depolymerizing agents that bind to colchicine site of beta-tubulin. Here, we screened a chemical library of substituted 4-H-chromenes and identified SP-6-27 to exhibit most potent anti-proliferative activity towards a panel of human cisplatin sensitive and resistant OVCA cell lines with 50% inhibitory concentration (IC50; mean ± SD) ranging from 0.10 ± 0.01 to 0.84 ± 0.20 μM. SP-6-27 exhibited minimum cytotoxicity to normal ovarian epithelia. A pronounced decrease in microtubule density as well as G2/M cell cycle arrest was observed in SP-6-27 treated cisplatin sensitive/resistant OVCA cells. The molecular mechanism of SP-6-27 induced cell death revealed modulation in cell-cycle regulation by upregulation of growth arrest and DNA damage inducible alpha transcripts (GADD45). An enhanced intrinsic apoptosis was observed in OVCA cells through upregulation of Bax, Apaf-1, caspase-6, -9, and caspase-3. In vitro wound healing assay revealed reduced OVCA cell migration upon SP-6-27 treatment. Additionally, SP-6-27 and cisplatin combinatorial treatment showed enhanced cytotoxicity in chemo-sensitive/resistant OVCA cells. Besides effect on cancer cells, SP-6-27 further restrained angiogenesis by inhibiting capillary tube formation by human umbilical vein endothelial cells (HUVEC). Together, these findings show that the chromene analog SP-6-27 is a novel chemotherapeutic agent that offers important advantages for the treatment of ovarian cancer.
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影响因子：
7.2
作者：
McIlwain, David R.;Berger, Thorsten;Mak, Tak W.
通讯作者：
Mak, Tak W.
DOI：
10.2147/ijwh.s30231
发表时间：
2013
期刊：
International journal of women's health
影响因子：
--
作者：
Kemp Z;Ledermann J
通讯作者：
Ledermann J
影响因子：
--
作者：
Ibrahim SA;Katara GK;Kulshrestha A;Jaiswal MK;Amin MA;Beaman KD
通讯作者：
Beaman KD
影响因子：
7.3
作者：
Kemnitzer, W;Drewe, J;Cai, SX
通讯作者：
Cai, SX
DOI：
10.1083/jcb.51.3.752
发表时间：
1971-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goldman RD
通讯作者：
Goldman RD