Inhibition of SREBP-mediated lipid biosynthesis and activation of multiple anticancer mechanisms by platinum complexes: Ascribe possibilities of new antitumor strategies

Xue Bai; Amjad Ali; Na Wang; Zongwei Liu; Zhimin Lv; Zeqing Zhang; Xing Zhao; Huifang Hao; Yongmin Zhang; Faiz-Ur Rahman

doi:10.1016/j.ejmech.2021.113920

Inhibition of SREBP-mediated lipid biosynthesis and activation of multiple anticancer mechanisms by platinum complexes: Ascribe possibilities of new antitumor strategies

Eur J Med Chem. 2022 Jan 5:227:113920. doi: 10.1016/j.ejmech.2021.113920. Epub 2021 Oct 14.

Authors

Xue Bai¹, Amjad Ali², Na Wang¹, Zongwei Liu¹, Zhimin Lv¹, Zeqing Zhang¹, Xing Zhao¹, Huifang Hao³, Yongmin Zhang⁴, Faiz-Ur Rahman⁵

Affiliations

¹ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
² Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Peshawar, KPK, Pakistan; Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, People's Republic of China.
³ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China; School of Life Sciences, Inner Mongolia University, Hohhot, 010021, People's Republic of China.
⁴ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France. Electronic address: yongmin.zhang@upmc.fr.
⁵ Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, People's Republic of China. Electronic address: faiz@imu.edu.cn.

PMID: 34742012
DOI: 10.1016/j.ejmech.2021.113920

Abstract

Cancer is one of the most aggressive diseases with poor prognosis and survival rates. Lipids biogenesis play key role in cancer progression, metastasis and tumor development. Suppression of SREBP-mediated lipid biogenesis pathway has been linked with cancer inhibition. Platinum complexes bearing good anticancer effect and multiple genes activation properties are considered important and increase the chances for development of new platinum-based drugs. In this study, we synthesized pyridine co-ligand functionalized cationic complexes and characterized them using multiple spectroscopic and spectrophotometric methods. Two of these complexes were studied in solid state by single crystal X-ray analysis. The stability of these complexes were measured in solution state using ¹H NMR methods. These complexes were further investigated for their anticancer activity against human breast, lung and liver cancer cells. MTT assay showed potential cytotoxic activity in dose-dependent manner and decrease survival rates of cancer cells was observed upon treatment with these complexes. Biological assays results revealed higher cytotoxicity as compared to cisplatin and oxaliplatin. Further we studied C2, C6 and C8 in detailed mechanistic anticancer analyses. Clonogenic assay showed decrease survival of MCF-7, HepG2 and A549 cancer cells treated with C2, C6 and C8 as compared to control cells treated with DMSO. TUNEL assay showed more cell death, these complexes suppressed invasion and migration ability of cancer cells and decreased tumor spheroids formation, thus suggesting a potential role in inhibition of cancer metastasis and cancer stem cells formation. Mechanistically, these complexes inhibited sterol regulatory element-binding protein 1 (SREBP-1) expression in cancer cells in dose-dependent manner and thereby reduced lipid biogenesis to suppress cancer progression. Furthermore, expression level was decreased for the key genes LDLR, FASN and HMGCR, those required for sterol biosynthesis. Taken together, these complexes suppressed cancer cell growth, migration, invasion and spheroids formation by inhibiting SREBP-1 mediated lipid biogenesis pathway.

Keywords: Anticancer study; Cancer cell migration; Cancer cells stemness; Cell invasion; Platinum complexes; SREBP-1 inhibition.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lipid Metabolism / drug effects
Molecular Structure
Organoplatinum Compounds / chemical synthesis
Organoplatinum Compounds / chemistry
Organoplatinum Compounds / pharmacology*
Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors*
Sterol Regulatory Element Binding Protein 1 / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Organoplatinum Compounds
SREBF1 protein, human
Sterol Regulatory Element Binding Protein 1