THZ1, a covalent CDK7 inhibitor, enhances gemcitabine-induced cytotoxicity via suppression of Bcl-2 in urothelial carcinoma

Kuan-Lin Kuo; Wei-Chou Lin; Shing-Hwa Liu; Fu-Shun Hsu; Yu Kuo; Shih-Ming Liao; Shao-Ping Yang; Zuo-He Wang; Chen-Hsun Hsu; Kuo-How Huang

THZ1, a covalent CDK7 inhibitor, enhances gemcitabine-induced cytotoxicity via suppression of Bcl-2 in urothelial carcinoma

Am J Cancer Res. 2021 Jan 1;11(1):171-180. eCollection 2021.

Authors

Kuan-Lin Kuo^{1

2}, Wei-Chou Lin³, Shing-Hwa Liu¹, Fu-Shun Hsu^{4

5}, Yu Kuo⁶, Shih-Ming Liao², Shao-Ping Yang², Zuo-He Wang², Chen-Hsun Hsu², Kuo-How Huang²

Affiliations

¹ Graduate Institute of Toxicology, College of Medicine, National Taiwan University Taipei, Taiwan.
² Department of Urology, College of Medicine, National Taiwan University and National Taiwan University Hospital Taipei, Taiwan.
³ Department of Pathology, National Taiwan University Hospital Taipei, Taiwan.
⁴ Department of Urology, Yang Ming Branch of Taipei City Hospital Taipei, Taiwan.
⁵ Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University Taipei, Taiwan.
⁶ Department of Radiology and Nuclear Medicine, Taipei Veterans General Hospital Taipei, Taiwan.

PMID: 33520367
PMCID: PMC7840706

Abstract

Chemotherapy with gemcitabine plus cisplatin remains the mainstay of treatment for metastatic urothelial carcinoma (UC); however, drug resistance occurs in most patients and eventually leads to treatment failure. In this study, we investigated the role of cyclin-dependent kinase 7 (CDK7) regulation in the treatment of human UCs. Moreover, we studied the effect of THZ1, a CDK7 inhibitor, alone and in combination with gemcitabine, on UCs and explored the underlying mechanism. Immunohistochemical staining showed that CDK7 expression was significantly higher in UC tumors than in counterpart urothelium. THZ1 elicited dose-dependent cytotoxicity and apoptosis in two high-grade UC cells (BFTC905 and T24). THZ1 co-treatment potentiated gemcitabine-induced cytotoxicity with suppression of B-cell lymphoma 2 (Bcl-2). Studies with a xenograft nude mouse model also confirmed that THZ1 enhanced the antitumor effect of gemcitabine on UC. These findings provide important pilot data to target CDK7 or Bcl-2 for the treatment of UCs and for overcoming chemoresistance in UCs.

Keywords: Bcl-2; CDK7; THZ1; Urothelial carcinoma; gemcitabine.