Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model
Abstract
Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related morbidity in China, responsible for approximately 90% of all esophageal cancer cases. This stark statistic emphasizes the pressing need for more effective therapeutic approaches to combat this aggressive and often fatal disease. ESCC is characterized by rapid progression, high metastatic potential, and a poor prognosis, mainly due to delayed diagnoses and a lack of effective treatment options. As such, discovering new drug targets for both the prevention and treatment of ESCC is crucial for improving patient survival rates and outcomes.
A promising therapeutic target that has gained considerable attention is Mcl-1, an anti-apoptotic protein that plays a pivotal role in regulating cell survival, apoptosis, and cell cycle progression. Mcl-1 is often overexpressed in several cancers, including ESCC, where it contributes to tumor growth and resistance to cell death. Given its vital role in maintaining cell survival, Mcl-1 presents a potentially valuable target for therapeutic intervention in ESCC.
In this study, we employed a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model to evaluate the therapeutic efficacy of A-1210477, a small molecule inhibitor specifically targeting Mcl-1. Our objective was to determine whether A-1210477 could inhibit the development of ESCC by modulating Mcl-1 activity. We observed that A-1210477 treatment led to a significant reduction in ESCC formation and prevented animal weight loss in a dose-dependent manner. These findings suggest that A-1210477 may offer protective effects against the development and progression of ESCC.
Additional analysis revealed a substantial decrease in cellular proliferation in A-1210477-treated ESCC tissues, as indicated by reduced Ki67 expression, a well-established marker of cell proliferation. This suggests that A-1210477 effectively hampers tumor cell proliferation, a key feature of cancer progression. Furthermore, treatment with A-1210477 resulted in a marked increase in apoptotic cells within the ESCC tissues, as evidenced by enhanced cleaved caspase-3 staining. This indicates that A-1210477 triggers apoptosis, further supporting its potential as a therapeutic agent for ESCC.
Our study provides strong evidence that Mcl-1 plays a crucial role in ESCC development by promoting cell proliferation and preventing apoptosis. Inhibiting Mcl-1 with A-1210477 not only inhibits tumor growth but also induces cell death, underscoring the therapeutic potential of Mcl-1 inhibition for ESCC treatment. These results warrant further preclinical and clinical investigations of A-1210477 as a promising therapeutic option for ESCC. Moreover, the identification of Mcl-1 as a critical factor in ESCC pathogenesis opens up new opportunities for targeted therapies that could significantly improve the prognosis of patients suffering from this devastating disease.