卵巢癌是女性生殖器官常見的腫瘤之一,，發(fā)病率僅次于子宮頸癌和子宮體癌而列居第三位,。2011年,，僅在美國(guó)一國(guó)就有25,000名婦女被確診患有卵巢癌,，并且因罹患卵巢癌而死亡的人數(shù)就有15,000多,。
近日，來自美國(guó)癌癥研究人員發(fā)現(xiàn)：抗癌新藥二吲哚甲烷（DIM）能抑制卵巢癌細(xì)胞的生長(zhǎng),，誘導(dǎo)卵巢癌細(xì)胞凋亡,，抑制卵巢癌組織的增長(zhǎng)。
研究證明二吲哚甲烷能抑制轉(zhuǎn)錄因子STAT3的活性,，加強(qiáng)化療藥物--順鉑的抗癌活性,。
腫瘤細(xì)胞的生長(zhǎng)過程中伴隨著血管生成，二吲哚甲烷不僅能殺死癌細(xì)胞,，并且能抑制腫瘤的血管生成,。腫瘤微環(huán)境中的炎癥因子IL-6激活STAT轉(zhuǎn)錄因子后，促進(jìn)了腫瘤細(xì)胞的生長(zhǎng),。90%的卵巢癌患者體內(nèi)STAT3被激活,，二吲哚甲烷通過抑制IL-6的磷酸化降低STAT3的轉(zhuǎn)錄活性。
運(yùn)用順鉑進(jìn)行化療治療的腫瘤病人,，病情往往得不到有效控制,，即癌癥患者出現(xiàn)耐藥性。而順鉑的耐藥性與STAT3活性的增加有著密切聯(lián)系,。研究者發(fā)現(xiàn)：相比較于單獨(dú)使用順鉑組,，順鉑與二吲哚甲烷聯(lián)合對(duì)老鼠體內(nèi)腫瘤生長(zhǎng)的抑制率要高出50%左右。
化療藥物本身毒性很大,，并且有嚴(yán)重的不良副作用,。靶向作用于STAT3的二吲哚甲烷通過誘導(dǎo)癌細(xì)胞凋亡，增強(qiáng)順鉑的化療效果,。同時(shí)二吲哚甲烷對(duì)正常的卵巢細(xì)胞并沒有毒性,。二吲哚甲烷聯(lián)與順鉑聯(lián)用起到了減毒增效的作用。(生物谷 Bioon.com)
doi:10.1186/1741-7015-10-9
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Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3)
Prabodh K Kandala and Sanjay K Srivastava
Background
STAT-3 is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that Diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, the exact mechanism by which DIM induces growth suppressive effects was not yet understood and hence evaluated in this report.
Methods
Six human ovarian cancer cells and ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination of cisplatin.
Results
Diindolylmethane treatment induced apoptosis in all the six ovarian cancer cells. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. IL-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, diindolylmethane treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. Diindolylmethane treatment also inhibited cell invasion and angiogenesis by suppressing HIF-1alpha and VEGF. Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation.
Conclusion
These findings provide a rationale for further clinical investigation of diindolylmethane alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer.
