A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-Mediated Cell Death in Human Hepatocellular
Chun-Te Ho1, Yu-Jia Chang2, Li-Xi Yang3
1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan.
Abstract:
Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 values in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (ΔΨm) and caused DNA damage. Mechanistically, TCD activated protein kinase RNA-like endoplasmic reticular kinase and several transcription factors, including activating transcription factor (ATF) 6, ATF4, ATF3, and the CCAAT-enhancer binding protein homologous protein. These data clearly demonstrate that the antitumor activity of TCD is mechanistically linked to its capacity to trigger both intrinsic and extrinsic apoptotic cell death via endoplasmic reticular stress pathway. The potent antitumor activity of TCD was similarly demonstrated in a hepatocellular carcinoma xenograft model, where 5 and 10 mg/kg doses of TCD significantly arrested Hep-J5 and Mahlavu tumor growth. Our finding suggests that TCD is a promising therapeutic agent against hepatocellular carcinoma; further translational assessment of its clinical usage is warranted.
Insights
A novel agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), shows strong antitumor effects against liver cancer cells. TCD induces cell cycle arrest and apoptosis, warranting further clinical investigation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide.
- Novel therapeutic strategies are urgently needed to improve treatment outcomes for HCC.
- Microtubule-disrupting agents have shown promise in cancer therapy.
Purpose of the Study:
- To investigate the antitumor activity and underlying mechanisms of a novel compound, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD).
- To evaluate the efficacy of TCD in preclinical models of hepatocellular carcinoma.
Main Methods:
- In vitro studies using HCC cell lines (Hep-J5, Mahlavu) to assess cytotoxicity, cell cycle progression, mitochondrial membrane potential, and DNA damage.
- Analysis of endoplasmic reticulum (ER) stress pathway activation, including key kinases and transcription factors (ATF6, ATF4, ATF3, CHOP).
- In vivo efficacy assessment in a hepatocellular carcinoma xenograft mouse model.
Main Results:
- TCD demonstrated potent cytotoxicity against HCC cell lines with IC50 values in the nanomolar range.
- TCD induced G2/M cell cycle arrest, decreased mitochondrial membrane potential, and caused DNA damage in a dose- and time-dependent manner.
- TCD activated the ER stress pathway, leading to apoptosis via both intrinsic and extrinsic pathways. Significant tumor growth inhibition was observed in vivo.
Conclusions:
- TCD exhibits significant antitumor activity against hepatocellular carcinoma through ER stress-mediated apoptosis.
- TCD represents a promising therapeutic candidate for HCC, meriting further clinical evaluation.
- The novel mechanism of action provides a basis for developing new targeted therapies for liver cancer.
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