Increased sensitivity to the platelet‐derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF‐BB‐mediated signaling and STI571‐induced Akt inactivation

Abstract

The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. The effects of the PDGFR inhibitor STI571 on proliferation and PDGFR signaling were compared in chemosensitive and cisplatin-selected, chemoresistant sublines derived from glioma and from two other PDGFR-expressing tumors (ovarian carcinoma and neuroblastoma). The chemoresistant glioma U87/Pt cells were twofold more sensitive to STI571 growth-inhibitory effects than the chemosensitive U87 cells, and two- to threefold more sensitive than five unrelated glioma cell lines. The other two paired cell lines were equally responsive. Sensitization of U87/Pt cells correlated with upregulation of the PDGF-B isoform and with PDGF-BB-induced Akt overactivation, which was prevented by STI571. STI571 specifically inhibited PDGF-BB-, but not PDGF-AA- or stem cell factor-mediated signaling. In serum-containing medium, STI571 decreased phospho-Akt in U87/Pt cells, but not in U87, while activating extracellular signal-regulated kinase (Erk) in both. STI571 antiproliferative effects were partially reverted by constitutively active Akt. Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

“…17 As a tyrosine kinase inhibitor, imatinib mesylate has been found to be a potent inhibitor of both PDGFR-a and -β and their respective signaling pathways. [18][19][20] These data point to a significant role of PDGF receptors in imatinib mesylate-induced thrombocytopenia. Moreover, imatinib mesylate also has anti-proliferation and anti-differentiation effects on human mesenchymal stem/stromal cells, 21 which play an important role in supporting thrombopoiesis.…”

Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

“…Down-modulation of ERK1/2 phosphorylation has further been documented in NB cells with acquired resistance to CDDP or VCR. However, these cell lines were additionally characterised by a distinct Akt activation (Kotchetkov et al, 2005;Servidei et al, 2006). Therefore, although purely speculative, fine-tuned alterations of the ERK and Akt signalling system may be -at least partially -responsible for establishing VCR and CDDP, but not DOX resistance in our NB cell model.…”

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

“…ERK1/2 (p44/p42MAPK) plays a pivotal role in the integration of signals from extracellular stimuli regulating cell proliferation, differentiation and survival (25). Other relevant studies using glioma cell lines, including U87MG cells, have reported that the constitutive activation of ERK or Akt in the absence of a RTK inhibitor could be related to resistance against imatinib (7,28,30,31). The activation of ERK by imatinib treatment was found in malignant glioma cells, including U87MG (31), squamous carcinoma (32), Bcr-Abl positive CML CD34 + (33) and K562 cells (24).…”