Mcl-1 inhibitor suppresses tumor growth of esophageal squamous cell carcinoma in a mouse model

Abstract

Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China, accounting for 90% of all esophageal carcinoma cases. Hence, identifying drug targets for prevention and treatment of ESCC is essential. Due to its critical role in the regulation of cell apoptosis, Mcl-1 holds great potential as a target for treatment against ESCC. In current study, we used a 4-nitroquinoline-1-oxide (4-NQO)-induced ESCC mouse model of test whether A-1210477, a Mcl-1 small molecular inhibitor, could repress ESCC development. We showed that A-1210477 treatment decreased ESCC formation and animal weight loss in a dose dependent manner. We detected decreased cellular proliferation in A-1210477-treated ESCC tissue by Ki67 expression. Moreover, A-1210477 treatment increased the number of apoptotic cells in ESCC tissues. Our study clearly demonstrates the contribution of Mcl-1 to ESCC development through promoting cell proliferation and inhibition of apoptosis, and provides a strong evidence for further evaluation of A-1210477 for treating ESCC.

MCL-1 inhibition in cancer treatment

“… 60 A recent study shows that A-1210477 suppresses the formation of carcinogen 4-nitroquinoline oxide-induced esophageal squamous cell carcinoma in mice. 61 …”

A‑1210477, a selective MCL‑1 inhibitor, overcomes ABT‑737 resistance in AML

“…Jilg et al (32) demonstrated that in patients with high-risk myelodysplastic syndrome (MDS) or secondary (s)AML, antagonizing BCL-2 family anti-apoptotic proteins can promote apoptosis. ABT-199 and ABT-737, which are BH3 mimic small-molecules, inhibit multiple different types of tumor, such as non-small cell lung cancer (15), AML (7,8,13), lymphoma (4,16), multiple myeloma (12,16), neuroblastoma (17), HNSCC (6), hepatocellular carcinoma (10) and ESCC (18), in a BCL-2 and/or BCL-XL-dependent manner (13). Furthermore, researchers have developed BCL-XL-selective antagonists (33).…”

“…A-1210477 specifically binds MCL-1 and promotes apoptosis of cancer cells in an MCL-1-dependent manner (35). Lin et al (18) revealed that A-1210477 treatment decreases ESCC formation and animal weight loss in a dose-dependent manner. In addition, the authors of this study demonstrated that A-1210477 treatment increases the number of apoptotic cells in ESCC tissues, which provides evidence towards the contribution of MCL-1 to ESCC development by promoting cell proliferation and inhibition of apoptosis, providing a potential therapy option for MCL-1-selective antagonist in treating ESCC (18).…”

“…ABT-737 has a high affinity for BCL-2/BCL-XL and can promote apoptosis of malignant cells (12,13). The upregulation of anti-apoptotic BCL-2 family proteins is associated with multiple different types of tumor (14), including non-small cell lung cancer (15), AML (7,8,13), lymphoma (4,16), multiple myeloma (12,16), neuroblastoma (17), HNSCC (6), hepatocellular carcinoma (10) and esophageal squamous cell carcinoma (ESCC) (18).…”

“…Furthermore, it has previously been reported that BH3 mimetic MCL-1-selective antagonist could inhibit the expression of MCL-1 (26,27). A-1210477, which binds to MCL-1 with high affinity, was the first MCL-1-BH3-only antagonist (6,18).…”