樂衛瑪(Lenvatinib)透過抑制EGFR/ERK/P-38/NF-κB活性增加膀胱癌細胞對克莫(Cisplatin)的敏感性、誘導細胞凋亡並抑制轉移

蔣智宏¹、楊智迪²、劉威麟³、許斐婷^4*

¹衛福部立桃園醫院泌尿外科/研究發展部；²陽明交通大學附設醫院泌尿外科；³彰化秀傳醫院放射腫瘤科；⁴中國醫藥大學生物技術學系

Lenvatinib enhances Cisplatin sensitivity, induces apoptosis and inhibits metastasis in bladder cancer cells through inactivation of EGFR/ERK/P-38/NF-κB signaling

Chih-Hung Chiang¹、Jr-Di Yang²、Wei-Lin Liu³、Fei-Ting Hsu^4*

¹ Division of Urology, Department of Surgery, and Department of Research and Development, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan；² Division of Urology, Department of Surgery, National Yang-Ming Chiao Tung University Hospital, Yilan, Taiwan；³ Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan；⁴ Department of Biological Science and Technology, China Medical University, Taichung, Taiwan

Purpose：The persistent activation of the epidermal growth factor receptor (EGFR) leads to the activation of downstream oncogenic kinases and transcription factors, resulting in tumor progression and an increased resistance to cisplatin in bladder cancer (BC) cells. Lenvatinib, an oral multikinase inhibitor, has the potential to offer therapeutic benefits as an adjuvant treatment for BC patients. However, it is unclear whether lenvatinib has the capacity to inhibit BC progression by targeting EGFR/ERK/P-38/NF-κB mediated signaling.

Materials and Methods：We used cell viability, apoptosis assay, wound healing assay, invasion/migration assay, Western blotting assay, immunofluorescence staining, as well as animal experiments, to elucidate the efficacy of lenvatinib on in vitro and in vivo BC models.

Results：In vitro experiments, we found that lenvatinib may induce cytotoxicity and intrinsic/extrinsic apoptosis in BC cells and enhance the potential of cisplatin. In vivo studies using a mouse model of BC confirmed the antitumor efficacy of lenvatinib, demonstrating significant tumor growth suppression without inducing toxicity in normal tissues. Western blotting analysis and immunohistochemistry stain revealed EGF-phosphorylated EGFR and EGFR-mediated ERK/P-38/NF-κB signaling were suppressed by treatment with lenvatinib. In addition, lenvatinib also suppressed anti-apoptotic (MCL1, C-FLIP, and XIAP) and metastasis-related factors (Twist, Snail-1, ZEB-1, ZEB-2, and MMP-9) and promoted epithelial markers (E-cadherin) while reducing mesenchymal markers (N-cadherin).