Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb pathway in vitro and in vivo

Cell Cycle. 2021 Dec;20(23):2494-2506. doi: 10.1080/15384101.2021.1991121. Epub 2021 Oct 17.

Abstract

Cyclin-dependent kinases (CDKs) are hyperactive in many cancers and have served as cancer therapeutic targets for decades. Palbociclib (Palb) is the first approved CDK4/6 inhibitor to treat hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Acquired drug resistance is one obstacle of Palb be utilized in other cancer. CDK2 compensation of CDK4/6 loss is one of the causes that cancer cells are resistant to Palb. Hence, targeting multiple CDKs could be a novel strategy to prevent the drug resistance of cancer cells and expand the application of Palb in other cancer. In this study, we initially indicated Polyphyllin I (PPI) significantly inhibits non-small lung cancer cell (NSCLC) proliferation, promotes cell apoptosis in vitro and in vivo. Mechanistically, PPI can inhibit Rb through the p21/CDK2/Rb signaling pathway in NSCLC. A combination of PPI and Palb exerts a significant synergistic anti-cancer ability on NSCLC. Of note, PPI can reverse Palb drug resistance. Herein, we first time demonstrated PPI can disturb CDK2 function through upregulation of p21. The PPI effect on CDK2 provides a choice for a chemotherapeutic strategy for the elimination of NSCLC. Our study highlighted the clinical significance of simultaneously blocking of CDK2 and CDK4/6 for NSCLC treatment.

Keywords: CDK2; Non-small cell lung cancer; polyphyllin I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Cyclin-Dependent Kinase 2* / metabolism
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Diosgenin* / analogs & derivatives
  • Humans
  • Lung Neoplasms* / drug therapy
  • Piperazines* / pharmacology
  • Pyridines* / pharmacology
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Piperazines
  • Pyridines
  • Retinoblastoma Protein
  • polyphyllin I
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • palbociclib
  • Diosgenin

Grants and funding

This study was supported by the Yunnan Applied Basic Res of Combined Foundation of Yunnan Province Science &Technology Dept. and Kunming Medical University [2017FE467(−186), 2018FE001(−069], 2019FE001-064]. Zhanjiang Science and Technology Bureau Competitive Science and Technology Project[2020A100302]. Yunnan Applied Basic Res. of Combined Foundation of Yunnan Province Science & Technology Dept, Yunnan Univ. of Chinese Medicine [2018FF001-026, 2019FF002-050, −040), 2018FF001-016, 2018FF001-079]. The National Natural Science Foundation of China [82060862, 81860881, 81960666, 81960835]. General project of Yunnan applied basic research program[2019FB118]. Guizhou Science & Technology Department [QKHJC (2017)1171]. The program Innovative Research Team in Science and Technology in Yunnan Province [202005AE160004] .Yunnan Scholar of Yunling [YNWR-YLXZ-2019-019] and Yunnan Key Project [2019FA033].