Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells

• Published in: Biomedicine (Taipei) Vol. 13; no. 4; pp. 20 - 31
• Main Authors: Hour, Mann-Jen, Tsai, Fuu‑ Jen, Lai, I-Lu, Tsao, Je-Wei, Chiang, Jo-Hua, Chiu, Yu-Jen, Lu, Hsing-Fang, Juan, Yu‑ Ning, Yang, Jai-Sing, Tsai, Shih-Chang
• Format: Journal Article
• Language: English
• Published: China (Republic : 1949- ) China Medical University 01.01.2023
• Subjects: Original; HMJ-38; Apoptotic cell death; Autophagy; Gemcitabine-resistance MIA-PaCa-2 pancreatic cancer cells (MIA-GR100); Epidermal growth factor receptor (EGFR)
• ISSN: 2211-8039; 2211-8020; 2211-8039
• DOI: 10.37796/2211-8039.1423

Gemcitabine is frequently utilized to treat pancreatic cancer. The purpose of our study was to create a gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cell line (MIA-GR100) and to evaluate the anti-pancreatic cancer efficacy of HMJ-38, a new quinazolinone analogue. Compared to their parental counterparts, MIA-PaCa-2, established MIA-GR100 cells were less sensitive to gemcitabine. MIA-GR100 cell viability was not affected by 10, 50 and 100 nM gemcitabine concentrations. HMJ-38 reduced MIA-GR100 cell growth and induced autophagy and apoptosis. When stained with monodansylcadaverine (MDC), acridine orange (AO), and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), MIA-GR100 cells shrunk, punctured their membranes, and produced autophagy vacuoles and apoptotic bodies. Combining chloroquine (CQ) and 3-methyladenine (3-MA) with HMJ-38 dramatically reduced cell viability, indicating that autophagy function as a cytoprotective mechanism. MIA-GR100 cells treated with both z-VAD-FMK and HMJ-38 were much more viable than those treated with HMJ-38 alone. HMJ-38 promotes apoptosis in MIA-GR100 cells by activating caspases. Epidermal growth factor receptor (EGFR) is one of HMJ-38's principal targets, as determined target screening with network prediction. HMJ-38 also inhibited EGFR kinase activity and EGFR-associated signaling in MIA-GR100 cells. HMJ-38 may be an effective chemotherapeutic adjuvant for gemcitabine-resistant pancreatic cancer cells, in which it induces an antitumor response.