Related Experiment Video

Updated: May 15, 2026

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration
11:13

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration

Published on: June 9, 2023

PI3K inhibition enhances doxorubicin-induced apoptosis in sarcoma cells

Diana Marklein1, Ulrike Graab, Ivonne Naumann

  • 1Institute of Human Genetics, University Medical Center, Goettingen, Germany.

Plos One
|January 10, 2013
PubMed

Insights

The dual PI3K/mTOR inhibitor PI103 enhances doxorubicin (DOX) efficacy in sarcoma by activating apoptosis pathways. PI3K inhibition shows promise for sensitizing tumor cells to anthracyclines like DOX.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Sarcoma treatment often involves chemotherapy, but resistance can limit efficacy.
  • Doxorubicin (DOX) is a common anthracycline chemotherapy agent.
  • Identifying agents to overcome drug resistance and enhance chemotherapy effectiveness is crucial.

Purpose of the Study:

  • To identify a drug that sensitizes sarcoma cells to doxorubicin (DOX).
  • To investigate the mechanism by which this sensitization occurs.
  • To evaluate the potential of PI3K inhibition as a general strategy to enhance anthracycline efficacy.

Main Methods:

  • Screening for drugs that enhance DOX efficacy in sarcoma cell lines.
  • Assessing the effects of PI103 and DOX combination on apoptosis induction.
  • Measuring the expression of drug resistance markers (MDR1, MRP1).
  • Analyzing the activation of apoptotic pathways (Bax, mitochondrial pathway, caspase 3).
  • Evaluating combination therapy in sarcoma xenograft models in mice.

Main Results:

  • The dual PI3K/mTOR inhibitor PI103 enhanced DOX efficacy in multiple sarcoma cell lines.
  • PI103 decreased MDR1 and MRP1 expression, leading to increased DOX accumulation.
  • Enhanced apoptosis was independent of DOX accumulation and mTOR inhibition.
  • Combination treatment activated the mitochondrial apoptosis pathway, Bax, and caspase 3.
  • Caspase 3 activation was observed in vivo with a PI3K inhibitor (GDC-0941) and DOX.

Conclusions:

  • PI3K inhibition, exemplified by PI103 and GDC-0941, enhances DOX-induced apoptosis in sarcoma.
  • The pro-apoptotic effect is mediated through the activation of Bax, mitochondrial pathway, and caspase 3.
  • PI3K inhibition represents a potential general strategy to sensitize various tumor cells, including neuroblastoma and glioblastoma, to anthracyclines.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...