Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing
Sayaka I Yamaguchi1,2, Arisa Ueki1, Eiji Sugihara1,3
1Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, Japan.
Abstract:
Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.
Insights
Novel therapies are needed for osteosarcoma (OS), a common bone cancer. Targeting platelet-derived growth factor-BB (PDGF-BB) with imatinib shows promise, especially when combined with chemotherapy, to improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma (OS) is the most common primary bone malignancy with a poor prognosis for chemotherapy-resistant patients.
- Novel therapeutic strategies are crucial for improving outcomes in OS.
- A mouse model of OS revealed the significant role of platelet-derived growth factor-BB (PDGF-BB).
Purpose of the Study:
- To investigate the role of PDGF-BB signaling in OS.
- To evaluate the efficacy of the PDGF receptor inhibitor imatinib in OS treatment.
- To explore combination therapies for enhanced anti-OS effects.
Main Methods:
- Enzyme-linked immunosorbent assay (ELISA) screening of mouse OS tumor lysates.
- Analysis of PDGF-BB and PDGF receptor beta expression in OS cells and surrounding tissues.
- In vitro studies on OS cell survival pathways (MEK-ERK, PI3K-AKT) with PDGF-BB and imatinib.
- In vivo studies assessing the antitumor effects of imatinib alone and in combination with adriamycin in mice.
Main Results:
- PDGF-BB was highly expressed in OS tumor lysates, with its receptor (PDGF receptor beta) highly expressed on OS cells.
- PDGF-BB promoted OS cell survival via MEK-ERK and PI3K-AKT pathways, inhibited by imatinib.
- Imatinib's effects were masked by serum; it showed no antitumor effect alone in vivo.
- Combination therapy with imatinib and adriamycin demonstrated synergistic antiproliferative effects in vivo.
Conclusions:
- PDGF-BB signaling is a potential therapeutic target in osteosarcoma.
- Imatinib efficacy is context-dependent, requiring specific conditions or combination therapies.
- Combining imatinib with other agents, like adriamycin, can overcome resistance and enhance anti-tumor activity in OS.
More Related Videos
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
08:57Sample Extraction and Simultaneous Chromatographic Quantitation of Doxorubicin and Mitomycin C Following Drug Combination Delivery in Nanoparticles to Tumor-bearing Mice
Published on: October 5, 2017
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle
01:27Combined Effects of Drugs: Synergism
Such synergistic combinations...