DZW-310, a novel phosphoinositide 3-kinase inhibitor, attenuates the angiogenesis and growth of hepatocellular carcinoma cells via PI3K/AKT/mTOR axis

Yuting Wu; Xiangbo Xu; Mingyue Liu; Xiaochun Qin; Qiong Wu; Huaiwei Ding; Qingchun Zhao

doi:10.1016/j.bcp.2022.115093

DZW-310, a novel phosphoinositide 3-kinase inhibitor, attenuates the angiogenesis and growth of hepatocellular carcinoma cells via PI3K/AKT/mTOR axis

Biochem Pharmacol. 2022 Jul:201:115093. doi: 10.1016/j.bcp.2022.115093. Epub 2022 May 14.

Authors

Yuting Wu¹, Xiangbo Xu¹, Mingyue Liu¹, Xiaochun Qin¹, Qiong Wu¹, Huaiwei Ding², Qingchun Zhao³

Affiliations

¹ Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, Guangdong Province 518055, PR China. Electronic address: 102030310@syphu.edu.cn.
³ Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, Liaoning Province 110016, PR China. Electronic address: zhaoqingchun@syphu.edu.cn.

PMID: 35580648
DOI: 10.1016/j.bcp.2022.115093

Abstract

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide with high lethality and prevalence. The deregulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an indispensable role in mediating the progression of HCC. Among them, PI3K acts as the most pivotal initiator, contributing to multiple malignant biological processes, like proliferation, apoptosis and angiogenesis. Many PI3K inhibitors (PI3Kis) have been proved or proceeded into clinical as antineoplastic drugs. Nevertheless, the application of PI3Kis for the treatment of HCC remains a blank. Accordingly, our study identified a novel PI3Ki (DZW-310) with strong anti-HCC activity in vitro and in vivo. This study aimed to evaluate its anti-HCC effect and elucidate its potential mechanism. Our current results revealed that DZW-310 significantly attenuated HCC cell growth through promoting intrinsic apoptosis and G0/G1 phase cell arrest. Moreover, DZW-310 suppressed angiogenesis by regulating the HIF-1α/VEGFA axis. Further mechanistic investigation demonstrated that DZW-310, functioned as a PI3Ki, exerted strong anti-HCC activity by acting on PI3Kα (a major subtype of PI3K) and ulteriorly deactivating the PI3K/AKT/mTOR pathway. Collectively, our studies identified that DZW-310 is expected to become a promising HCC therapeutic agent and broaden clinical application of PI3Ki in HCC chemotherapy.

Keywords: Angiogenesis; DZW-310; Growth; Hepatocellular carcinoma (HCC); PI3K/AKT/mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Carcinoma, Hepatocellular* / blood supply
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Liver Neoplasms* / blood supply
Liver Neoplasms* / drug therapy
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / pathology
Phosphatidylinositol 3-Kinase* / metabolism
Phosphoinositide-3 Kinase Inhibitors* / pharmacology
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction / drug effects
TOR Serine-Threonine Kinases* / metabolism

Substances

Phosphoinositide-3 Kinase Inhibitors
MTOR protein, human
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases