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Study of Protein-protein Interactions in Autophagy Research
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Synergistic effect of Dactolisib/Lys05 combination on autophagy in A549 cells

Mohammad Abdelwahab1, Hesham Saeed1, Nefertiti Elnikhely1

  • 1Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.

Acta Biochimica Polonica
|September 7, 2023
PubMed

Insights

Combining PI3K/AKT inhibitors with autophagy inhibitors like Dactolisib and Lys05 enhances anti-cancer effects. This synergistic approach targets KRAS-mutated lung cancer cells more effectively than monotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS mutations present a therapeutic challenge in cancer, necessitating novel treatment strategies.
  • Targeting the PI3K/AKT/mTOR pathway offers antiproliferative and apoptotic effects but can induce compensatory autophagy, limiting efficacy.
  • Combining kinase inhibitors with autophagy inhibitors may overcome resistance and enhance therapeutic outcomes.

Purpose of the Study:

  • To investigate the synergistic effects of Dactolisib (a PI3K/mTOR inhibitor) and Lys05 (an autophagy inhibitor) on cancer cell lines.
  • To determine the optimal combination ratio for Dactolisib and Lys05 using CompuSyn software.
  • To evaluate the impact of this combination on cell death, proliferation, and autophagy markers.

Main Methods:

  • Cell viability assays were performed on MCF-7 (breast cancer) and A549 (lung cancer) cells.
  • Dose-response studies and synergistic effect analysis were conducted using CompuSyn software.
  • Gene and protein expression analysis (ELISA, Western blot, flow cytometry) assessed autophagic, proliferative, and apoptotic markers.

Main Results:

  • A 2:1 ratio of Lys05 to Dactolisib showed a synergistic effect on A549 cell death and proliferation.
  • The combination therapy significantly modulated autophagic, proliferative, and apoptotic gene and protein markers.
  • Enhanced therapeutic benefits were observed in A549 cells treated with the combination compared to monotherapy.

Conclusions:

  • The combination of PI3K/AKT kinase inhibitors and autophagy inhibitors demonstrates superior therapeutic potential against KRAS-related cancers.
  • Synergistic inhibition of autophagy alongside PI3K/AKT signaling enhances anti-cancer efficacy in lung cancer models.
  • This combinatorial strategy offers a promising approach for improving treatment outcomes in patients with KRAS mutations.

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