4.6 Article

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

Journal

CELL CYCLE
Volume 20, Issue 23, Pages 2494-2506

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2021.1991121

Keywords

Non-small cell lung cancer; polyphyllin I; CDK2

Categories

Funding

  1. Yunnan Applied Basic Res of Combined Foundation of Yunnan Province Science Technology Dept
  2. Kunming Medical University [2017FE467(-186), 2018FE001(-069], 2019FE001-064]
  3. Zhanjiang Science and Technology Bureau Competitive Science and Technology Project [2020A100302]
  4. Yunnan Applied Basic Res. of Combined Foundation of Yunnan Province Science & Technology Dept, Yunnan Univ. of Chinese Medicine [2018FF001-026, 2019FF002-050, 2019FF002-040, 2018FF001-016, 2018FF001-079]
  5. National Natural Science Foundation of China [82060862, 81860881, 81960666, 81960835]
  6. General project of Yunnan applied basic research program [2019FB118]
  7. Guizhou Science & Technology Department [QKHJC (2017)1171]
  8. program Innovative Research Team in Science and Technology in Yunnan Province [202005AE160004]
  9. Yunnan Key Project [2019FA033]
  10. [YNWR-YLXZ-2019-019]

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Our study found that Polyphyllin I (PPI) significantly inhibits proliferation and promotes apoptosis in non-small cell lung cancer cells (NSCLC). PPI inhibits Rb through the p21/CDK2/Rb signaling pathway in NSCLC, and in combination with Palb, it shows a significant synergistic anti-cancer effect on NSCLC, as well as reversing Palb drug resistance. This suggests that targeting both CDK2 and CDK4/6 may have clinical significance in the treatment of NSCLC.
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.

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