ZDQ-0620, a Novel Phosphatidylinositol 3-Kinase Inhibitor, Inhibits Colorectal Carcinoma Cell Proliferation and Suppresses Angiogenesis by Attenuating PI3K/AKT/mTOR Pathway.

Xiaochun Qin,Xiangbo Xu,Yuting Wu,Bo Xing,Chang Xu,Huaiwei Ding,Mingyue Liu,Qingchun Zhao

doi:10.3389/fonc.2022.848952

Abstract

The PI3K/AKT pathway plays a central role in human cancers, aberrant activation of this pathway is associated with tumorigenesis, cancer progression and angiogenesis. Based on the importance of the PI3K/AKT pathway in malignancies, we developed a 4-aminoquinazoline derivative, ZDQ-0620, initially envisioned as a novel pan-PI3K inhibitor. This study aimed to evaluate the potential target of ZDQ-0620 and its anticancer effect in human colorectal carcinoma (CRC). PI3K-kinase activity test showed IC50 of ZDQ-0620 against PI3Ka was 0.5 nM; molecular docking, CETSA assay and western blotting was further performed to predict ZDQ-0620 was a PI3K/AKT pathway inhibitor by targeting PI3K. To identify the effect of ZDQ-0620 on CRC cells, Sulforhodamine B (SRB) assay, flow cytometry, and Cell morphology analysis were conducted. The results showed that ZDQ-0620 inhibited the proliferation, migration and invasion of CRC cells, induced apoptosis through G0/G1 cell cycle arrest and mitochondrial pathway. Additionally, ZDQ-0620 inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In vivo, neovascularization of rat aortic ring and chick chorioallantoic membrane (CAM) induced by VEGF was diminished when treated with ZDQ-0620. These results indicate that ZDQ-0620 induce apoptosis and anti-angiogenesis via inhibits the PI3K/AKT pathway. We suggest that the great potential of ZDQ-0620 as an effective treatment candidate against CRC.

Highlights

Colorectal cancer, one of the most common cancers worldwide, has been a serious threat to human health [1]
The PI3K/AKT/mTOR pathway plays a critical role in the occurrence and progression of colorectal cancer [19, 20]
Genes in the PI3K/AKT/mTOR pathway change most frequently in human cancers [22]. Due to these somatic mutations, abnormal activation of this pathway is associated with cell transformation, tumorigenesis, angiogenesis and cancer progression [10, 23]

Summary

Introduction

Colorectal cancer, one of the most common cancers worldwide, has been a serious threat to human health [1]. There are about 1.36 million new cases of colorectal cancer in the world every year, which is the third most common malignant tumor globally [2]. The incidence of colorectal cancer ranks the third in men and the second in women. Every year about 690,000 cases of death, ranking the fourth malignancy [3]. Despite advances in diagnosis and treatment over the past few decades, colorectal cancer remains a major health problem and a significant socioeconomic burden [4]. A few cases of CRC are detected early enough, so early accurate diagnosis and targeted treatment plan is important, such as surgery, chemotherapy, and radiotherapy [5, 6]. Rapid tumor growth, characterized by rapid progression and poor prognosis, is a major problem affecting the treatment of CRC [7]

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