The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.
The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.
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DOI：
10.1002/1878-0261.12756
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发表时间：
2020-10
影响因子：
6.6
通讯作者：
Souček K
中科院分区：
文献类型：
--
作者：
Drápela S;Khirsariya P;van Weerden WM;Fedr R;Suchánková T;Búzová D;Červený J;Hampl A;Puhr M;Watson WR;Culig Z;Krejčí L;Paruch K;Souček K
由于不治之症转移性去势抵抗前列腺癌(MCRPC)患者的治疗选择相当有限，因此需要新的有效的治疗方案。Checkpoint kinase1(Checkpoint kinase1，CHK1)是一种高度保守的蛋白激酶，参与DNA损伤反应(DDR)途径，防止DNA损伤积累，控制正常的基因组复制。CHK1与前列腺癌的发生、发展和致死性有关，因此，CHK1抑制剂SCH900776(也称为MK-8776)和更有效的SCH900776类似物MU380可能在前列腺癌的治疗中有临床应用。协同诱导DNA损伤和抑制CHK1是一种很有前途的治疗方法，已在许多类型的恶性肿瘤中进行了测试，但尚未在耐药的mCRPC中进行测试。在这里，我们报告了这种治疗方法可以利用抗代谢药物吉西他滨(GEM)与CHK1抑制剂SCH900776和MU380在多西紫杉醇耐药(DR)mCRPC中的协同作用来开发。考虑到这些结果，在2D条件下，两种CHK1抑制剂都显著增强了一组化疗初治和匹配的DR PCA细胞株对GEM的敏感性。MU380与GEM的协同作用强于临床候选药物SCH900776。在所有患者来源的异种移植物3D培养中，MU380单独或与GEM联合使用显著减小了球体大小，增加了细胞凋亡，在DR模型中影响更大。联合治疗诱导G1期早期有丝分裂，导致有丝分裂灾难作为细胞凋亡的前驱阶段。最后，MU380单独或与GEM联合治疗显著抑制了PC339-DOC和PC346C-DOC小鼠异种移植模型的肿瘤生长。综上所述，我们的数据表明，代谢强健和选择性的CHK1抑制剂MU380可以绕过多西紫杉醇耐药，并在DR mCRPC模型中提高GEM的有效性。这种方法可能会减少GEM的剂量，从而将不良反应降至最低，并可能成为难治性DR mCRPC患者的一种治疗选择。由于转移性去势抵抗前列腺癌(MCRPC)的治疗选择有限，迫切需要新的治疗方法。在这里，我们发现检查点激酶1(CHK1)抑制剂MU380显著增强吉西他滨对多西他赛耐药的mCRPC模型的细胞毒性，导致有丝分裂灾难。这些数据为MU380在治疗mCRPC的临床环境中的应用提供了临床前的理论基础。
As treatment options for patients with incurable metastatic castration‐resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK‐8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339‐DOC and PC346C‐DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC. As the treatment options for metastatic castration‐resistant prostate cancer (mCRPC) are limited, novel therapeutic approaches are urgently needed. Here, we showed that checkpoint kinase 1 (CHK1) inhibitor MU380 significantly potentiates gemcitabine cytotoxicity in docetaxel‐resistant mCRPC models, resulting in mitotic catastrophe. These data provide a preclinical rationale for the application of MU380 in a clinical setting for the therapy of mCRPC.
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影响因子：
11.2
作者：
Koh, Siang-Boon;Courtin, Aurelie;Jodrell, Duncan I.
通讯作者：
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影响因子：
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作者：
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影响因子：
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Kote-Jarai, Z.
影响因子：
8.8
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Karanika S;Karantanos T;Li L;Wang J;Park S;Yang G;Zuo X;Song JH;Maity SN;Manyam GC;Broom B;Aparicio AM;Gallick GE;Troncoso P;Corn PG;Navone N;Zhang W;Li S;Thompson TC
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Thompson TC
影响因子：
10.1
作者：
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通讯作者：
Trbusek, Martin