CDK 抑制剂 Dinaciclib 对胆管癌的抗肿瘤和化疗增敏作用。

Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma and .

机构信息

Biomedical Science Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand.

Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.

出版信息

In Vivo. 2024 Sep-Oct;38(5):2284-2293. doi: 10.21873/invivo.13693.

DOI:10.21873/invivo.13693

PMID:39187317

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11363801/

Abstract

BACKGROUND/AIM: Cholangiocarcinoma (CCA) is a highly aggressive disease. Most of CCA patients are diagnosed in an advanced stage of the disease, when it is unresectable and there is chemoresistance, resulting in poor prognosis. However, effective therapeutic regimens and molecular targets for CCA remain poor. Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression. Aberrant CDK activation is a hallmark of cancer. Dinaciclib is a small molecule inhibitor of multiple CDKs, currently under clinical evaluation for treating advanced malignancies. The efficacy of anti-tumor activity of dinaciclib against chemotherapy resistant CCA cells was examined in vitro and in vivo.

MATERIALS AND METHODS

In this study, the effect of dinaciclib on growth and cell cycle in CCA cell lines were determined using the MTT assay and cell cycle analysis. The anti-tumor activity of dinaciclib was investigated in CCA-inoculated mice. In addition, the chemosensitizing effect of dinaciclib was investigated in gemcitabine-treated CCA cell lines.

RESULTS

Dinaciclib significantly suppressed cell proliferation, induced G/S phase cell cycle arrest and apoptosis of CCA cell lines. It significantly suppressed the growth of CCA cells in xenograft mouse models. We also found that dinaciclib significantly inhibited the growth of gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Furthermore, dinaciclib significantly enhanced the anti-tumor activity of gemcitabine in CCA cell lines.

CONCLUSION

Dinaciclib has the potential to be an effective therapeutic agent to control tumor cell growth of both parental and gemcitabine-resistant CCA cells.

摘要

背景/目的：胆管癌（CCA）是一种高度侵袭性的疾病。大多数 CCA 患者在疾病的晚期被诊断出来，此时疾病无法切除且存在化疗耐药性，导致预后不良。然而，针对 CCA 的有效治疗方案和分子靶点仍然有限。细胞周期蛋白依赖性激酶（CDKs）是细胞周期进展的关键调节酶。CDK 的异常激活是癌症的一个标志。 Dinaciclib 是一种多种 CDK 的小分子抑制剂，目前正在临床评估中用于治疗晚期恶性肿瘤。本研究旨在体外和体内研究 Dinaciclib 对化疗耐药 CCA 细胞的抗肿瘤活性。

材料和方法

在这项研究中，通过 MTT 测定法和细胞周期分析来确定 Dinaciclib 对 CCA 细胞系生长和细胞周期的影响。在 CCA 接种小鼠中研究了 Dinaciclib 的抗肿瘤活性。此外，还研究了 Dinaciclib 在吉西他滨治疗的 CCA 细胞系中的化疗增敏作用。

结果

Dinaciclib 显著抑制 CCA 细胞系的增殖，诱导 G1/S 期细胞周期阻滞和细胞凋亡。它显著抑制异种移植小鼠模型中 CCA 细胞的生长。我们还发现 Dinaciclib 显著抑制了吉西他滨耐药的 CCA 细胞系（KKU-213A-GemR 和 KKU-100-GemR）的生长。此外，Dinaciclib 显著增强了 CCA 细胞系中吉西他滨的抗肿瘤活性。