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Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
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Published on: September 5, 2018

A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth

Xiang Wang1, Jia-peng Li, Yan Yang

  • 1Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Acta Pharmacologica Sinica
|July 30, 2013
PubMed
Abstract

Insights

This study reveals that different tumor cells rely on specific phosphoinositide 3-kinase (PI3K) isoforms for growth. Pan-PI3K inhibitors are effective for prostate cancer, while PI3Kδ inhibitors work for leukemia, guiding PI3K inhibitor selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Phosphoinositide 3-kinases (PI3Ks) are crucial signaling enzymes involved in cell growth and survival.
  • Class I PI3Ks, comprising α, β, γ, and δ isoforms, play diverse roles in various cancers.
  • Targeting PI3K isoforms with specific inhibitors offers a promising strategy for cancer therapy.

Purpose of the Study:

  • To determine the contribution of individual class I PI3K isoforms (α, β, γ, δ) to tumor cell proliferation.
  • To evaluate the efficacy of isoform-specific and pan-PI3K inhibitors in different cancer cell lines.
  • To guide the rational selection of PI3K inhibitors for specific cancer types.

Main Methods:

  • Established human rhabdomyosarcoma Rh30 cells expressing myristoylation (Myr)-tagged p110 subunits of PI3K isoforms.
  • Assessed PI3K activity by measuring phosphorylated Akt via Western blotting.
  • Validated isoform-specific PI3K activities using selective inhibitors and evaluated cell proliferation with SRB and CCK-8 assays.

Main Results:

  • Isoform-selective inhibitors demonstrated specific inhibition of Akt phosphorylation in Rh30-Myr-p110α, β, γ, δ cells.
  • A novel pan-PI3K inhibitor, WJD008, abrogated Akt phosphorylation by all class I PI3K isoforms.
  • Prostate cancer PC-3 cells showed reduced proliferation with pan-PI3K inhibition, while B cell leukemia Raji cells were sensitive to PI3Kδ or pan-PI3K inhibition.

Conclusions:

  • Rh30 cells expressing individual PI3K isoforms serve as a valuable model for assessing PI3K inhibitor selectivity.
  • Pan-PI3K inhibitors are effective for PC-3 prostate cancer cells, whereas PI3Kδ inhibitors are sufficient for Raji leukemia cells.
  • The distinct isoform dependencies of tumor cells support the tailored use of PI3K inhibitors in cancer treatment.

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