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4'-Demethylpodophyllotoxin functions as a mechanism-driven therapy by targeting the PI3K-AKT pathway in Colorectal

Jun Liu1, Dandong Luo2, Xiaochuan Chen3

  • 1Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, PR China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, PR China.

Translational Oncology
|December 4, 2024
PubMed

Insights

4'-demethylpodophyllotoxin (DOP), a Chinese herbal medicine derivative, effectively inhibits colorectal cancer (CRC) growth. DOP induces apoptosis and cell cycle arrest, showing therapeutic potential for CRC treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Natural Products Chemistry

Background:

  • Colorectal cancer (CRC) presents treatment challenges due to drug resistance and poor prognosis.
  • Novel therapeutic strategies are crucial for improving CRC patient outcomes.
  • Chinese herbal medicines offer a rich source for identifying potential anti-cancer compounds.

Purpose of the Study:

  • To identify effective Chinese herbal medicines for colorectal cancer (CRC) treatment.
  • To evaluate the anti-cancer properties of 4'-demethylpodophyllotoxin (DOP) against CRC.
  • To elucidate the molecular mechanisms underlying DOP's anti-tumor effects.

Main Methods:

  • High-throughput drug screening of Chinese herbal medicines.
  • In vitro assessment of DOP's effects on CRC cell lines and patient-derived tumor organoids.
  • RNA sequencing (RNA-seq) to analyze molecular pathways affected by DOP.
  • In vivo efficacy study using a DLD1-derived xenograft model.

Main Results:

  • 4'-demethylpodophyllotoxin (DOP) demonstrated significant time- and dose-dependent growth inhibition of CRC cells and organoids.
  • RNA-seq analysis revealed DOP activates the PI3K-AKT pathway, inducing tumor cell apoptosis and G2/M cell cycle arrest.
  • DOP treatment led to DNA damage in CRC cells.
  • In vivo studies confirmed DOP's ability to suppress CRC growth in the DLD1 xenograft model.

Conclusions:

  • 4'-demethylpodophyllotoxin (DOP) exhibits potent anti-tumor activity against colorectal cancer (CRC).
  • DOP's mechanism involves PI3K-AKT pathway activation, apoptosis induction, cell cycle arrest, and DNA damage.
  • DOP represents a promising therapeutic candidate for CRC treatment, warranting further investigation of podophyllotoxin derivatives.
Keywords:
4′-DemethylpodophyllotoxinChemoresistanceColorectal cancerPI3K-AKT pathway

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