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β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Shiyun Nie1, Lizhong Chang1, Ying Huang1

  • 1Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.

Natural Products and Bioprospecting
|January 3, 2024
PubMed

Insights

We identified Z86, a novel PI3Kα inhibitor, that effectively halts colorectal cancer (CRC) growth and migration by blocking the PI3K/Akt pathway and inhibiting Wnt signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Phosphoinositide 3-kinases (PI3Ks) are crucial lipid kinases regulating cell functions.
  • Aberrant PI3K/Akt/mTOR signaling is implicated in colorectal cancer (CRC) progression.
  • Targeting PI3K offers a potential therapeutic strategy for CRCs.

Purpose of the Study:

  • To identify and characterize novel inhibitors of PI3Kα.
  • To investigate the anti-cancer effects of a new compound, Z86, on colorectal cancer cells.
  • To elucidate the molecular mechanisms underlying Z86's action in CRCs.

Main Methods:

  • Compound screening and characterization of Z86 as a PI3Kα inhibitor (IC50 = 4.28 µM).
  • Binding confirmation using DARTS and CETSA assays.
  • Assessment of PI3K/AKT pathway modulation via immunofluorescence and western blotting.
  • Cell proliferation, cell cycle, apoptosis, and migration assays in CRC cell lines.

Main Results:

  • Z86 demonstrated potent inhibition of PI3Kα with confirmed binding.
  • Z86 significantly attenuated the PI3K/AKT signaling pathway.
  • Z86 inhibited CRC proliferation by inducing G0/G1 cell cycle arrest and reduced cell migration.
  • Z86 exhibited inhibitory effects on the Wnt signaling pathway.

Conclusions:

  • Z86 is a novel and potent PI3Kα inhibitor with significant anti-cancer activity against colorectal cancer.
  • Z86 effectively suppresses CRC growth and metastasis through cell cycle arrest and pathway inhibition.
  • The findings highlight Z86 as a promising therapeutic candidate for colorectal cancer treatment, acting via PI3Kα and Wnt pathway modulation.
Keywords:
Cell cycle arrestColorectal cancerPI3KProliferationZ86

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