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

• Published in: European journal of medicinal chemistry Vol. 276; p. 116635
• Main Authors: Wang, Qiang, Ma, Fangchao, Wang, Jingchen, Xu, Hongde, Li, Keyan, Cheng, Yung-Yi, Chen, Xiqiang, Qu, Shuhao, Wei, Tingting, Hao, Xiaofei, Kong, Mingyue, Xie, Chengping, Wang, Wei, Wang, Yanli, Jeong, Lak Shin
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.10.2024
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis - drug effects; autophagy; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hepatocellular carcinoma cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Mice; Mice, Nude; Molecular Structure; Nucleosides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pentacyclic triterpene; Structure-Activity Relationship; Transcriptome - drug effects; Transcriptome sequencing analyses; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Zebrafish; Nucleosides; Antitumor activity; Hepatocellular carcinoma cells; autophagy; Pentacyclic triterpene; Transcriptome sequencing analyses
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116635

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. [Display omitted] •Conjugated triterpenes with nucleoside derivatives exhibited increased anti-tumor activity and solubility.•The methylated betulonic acid-azidothymidine derivative inducing autophagy and apoptosis in hepatocellular carcinoma cells.•Transcriptomic studies revealed its activation of autophagy by suppressing the PI3K/Akt/mTOR pathway in SMMC-7721 cells.