2. Academic Validation
  3. Antitumor activity and transcriptome sequencing (RNA-seq) analyses of hepatocellular carcinoma cells in response to exposure triterpene-nucleoside conjugates

Antitumor activity and transcriptome sequencing (RNA-seq) analyses of hepatocellular carcinoma cells in response to exposure triterpene-nucleoside conjugates

  • Eur J Med Chem. 2024 Jun 28:276:116635. doi: 10.1016/j.ejmech.2024.116635.
Qiang Wang 1,  Fangchao Ma 2,  Jingchen Wang 2,  Hongde Xu 2,  Keyan Li 3,  Yung-Yi Cheng 4,  Xiqiang Chen 5,  Shuhao Qu 6,  Tingting Wei 3,  Xiaofei Hao 5,  Mingyue Kong 3,  Chengping Xie 5,  Wei Wang 7,  Yanli Wang 8,  Lak Shin Jeong 9
Affiliations

Affiliations

  • 1 Henan Biotechnology Development Center, BGI College & Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, 450052, China; High & New Technology Research Center, Henan Academy of Sciences, Zhengzhou, 450002, China; College of Pharmacy, Seoul National University, Seoul, 08820, South Korea. Electronic address: wangqiangno1@hotmail.com.
  • 2 Henan Biotechnology Development Center, BGI College & Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, 450052, China.
  • 3 National Health Commission Key Laboratory of Birth Defect Prevention, Henan Provincial People's Hospital, Zhengzhou, 450002, China.
  • 4 School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan; Natural Products Research Laboratories, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7568, USA.
  • 5 High & New Technology Research Center, Henan Academy of Sciences, Zhengzhou, 450002, China.
  • 6 College of Pharmacy, Seoul National University, Seoul, 08820, South Korea.
  • 7 Henan Natural Product Biotechnology Co. Ltd., Zhengzhou, 450002, China. Electronic address: bioww@foxmail.com.
  • 8 National Health Commission Key Laboratory of Birth Defect Prevention, Henan Provincial People's Hospital, Zhengzhou, 450002, China. Electronic address: hblyfe@163.com.
  • 9 College of Pharmacy, Seoul National University, Seoul, 08820, South Korea. Electronic address: lakjeong@snu.ac.kr.
PMID: 38964258 DOI: 10.1016/j.ejmech.2024.116635
Abstract

Fifteen betulonic/betulinic acid conjugated with nucleoside derivatives were synthesized to enhance antitumor potency and water solubility. Among these, the methylated betulonic acid-azidothymidine compound (8c) exhibited a broad-spectrum of antitumor activity against three tested tumor cell lines, including SMMC-7721 (IC50 = 5.02 μM), KYSE-150 (IC50 = 5.68 μM), and SW620 (IC50 = 4.61 μM) and along with lower toxicity (TC50 > 100 μM) estimated by zebrafish embryos assay. Compared to betulinic acid (<0.05 μg/mL), compound 8c showed approximately 40-fold higher water solubility (1.98 μg/mL). In SMMC-7721 cells, compound 8c induced Autophagy and Apoptosis as its concentration increased. Transcriptomic Sequencing analysis was used to understand the potential impacts of the underlying mechanism of 8c on SMMC-7721 cells. Transcriptomic studies indicated that compound 8c could activate Autophagy by inhibiting the PI3K/Akt pathway in SMMC-7721 cells. Furthermore, in the xenograft mice study, compound 8c significantly slowed down the tumor growth, as potent as paclitaxel treated group. In conclusion, methylated betulonic acid-azidothymidine compound (8c) not only increases water solubility, but also enhances the potency against hepatocellular carcinoma cells by inducing Autophagy and Apoptosis, and suppressing the PI3K/Akt/mTOR signaling pathway.

Keywords

Antitumor activity; Hepatocellular carcinoma cells; Nucleosides; Pentacyclic triterpene; Transcriptome sequencing analyses; autophagy.

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