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Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition.

Jayanthan A, Bernoux D, Bose P, Riabowol K, Narendran A - Cancer Cell Int. (2011)

Bottom Line: The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination.Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied.In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Pre-clinical and Drug Discovery Studies, Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) and Division of Pediatric Oncology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, T3B 6A8, Canada. anarendr@ucalgary.ca.

ABSTRACT

Background: Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT) constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines.

Results: AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination.

Conclusions: In addition to previously described involvement of insulin like growth factor (IGF) family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

No MeSH data available.


Related in: MedlinePlus

Expression of targets of sorafenib and sunitinib in AT/RT cell lines. Using Western blot analysis, it was determined that AT/RT cell lines express receptor tyrosine kinase targets of sorafenib and sunitinib: c-Kit, PDGF-Rβ, VEGFR2 and Flt-3. In addition, these cell lines express intracellular targets of sorafenib: c-Raf and p38α.
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Figure 2: Expression of targets of sorafenib and sunitinib in AT/RT cell lines. Using Western blot analysis, it was determined that AT/RT cell lines express receptor tyrosine kinase targets of sorafenib and sunitinib: c-Kit, PDGF-Rβ, VEGFR2 and Flt-3. In addition, these cell lines express intracellular targets of sorafenib: c-Raf and p38α.

Mentions: The presence of a multitude of cytokines in the culture supernatants of the AT/RT cell lines indicated the potential for autocrine or paracrine growth sustaining processes utilizing these molecules. Therefore, we wanted to investigate the effects of agents that have been shown to interfere with the activity of such receptor pathways. Sorafenib and sunitinib have been shown to inhibit the activity of a number of cytokine receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit) and FMS-like tyrosine kinase-3 (Flt-3) [13,14]. In the next set of experiments, the three AT/RT cell lines were evaluated for sensitivity to sorafenib and sunitinib by in vitro cytotoxicity assays. Figures 1A and 1B show the dose dependent inhibition of AT/RT cell growth by these agents. From these data, IC50 values were calculated and presented in Table 2. IC50 values for each cell line ranged from 2.8 to 3.6 µM for sorafenib and 3.2 to 3.7 µM for sunitinib. As a means to further support the targeted inhibition of receptor pathways by sorafenib and sunitinib, the expression of proteins targeted by these inhibitors was determined by Western blot analysis. It was found that all three AT/RT cell lines expressed receptor tyrosine kinases c-Kit, PDGF-Rβ, VEGFR2 and Flt-3, as well as the intracellular targets of sorafenib, c-Raf and p38α (Figure 2).


Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition.

Jayanthan A, Bernoux D, Bose P, Riabowol K, Narendran A - Cancer Cell Int. (2011)

Expression of targets of sorafenib and sunitinib in AT/RT cell lines. Using Western blot analysis, it was determined that AT/RT cell lines express receptor tyrosine kinase targets of sorafenib and sunitinib: c-Kit, PDGF-Rβ, VEGFR2 and Flt-3. In addition, these cell lines express intracellular targets of sorafenib: c-Raf and p38α.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3278350&req=5

Figure 2: Expression of targets of sorafenib and sunitinib in AT/RT cell lines. Using Western blot analysis, it was determined that AT/RT cell lines express receptor tyrosine kinase targets of sorafenib and sunitinib: c-Kit, PDGF-Rβ, VEGFR2 and Flt-3. In addition, these cell lines express intracellular targets of sorafenib: c-Raf and p38α.
Mentions: The presence of a multitude of cytokines in the culture supernatants of the AT/RT cell lines indicated the potential for autocrine or paracrine growth sustaining processes utilizing these molecules. Therefore, we wanted to investigate the effects of agents that have been shown to interfere with the activity of such receptor pathways. Sorafenib and sunitinib have been shown to inhibit the activity of a number of cytokine receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit) and FMS-like tyrosine kinase-3 (Flt-3) [13,14]. In the next set of experiments, the three AT/RT cell lines were evaluated for sensitivity to sorafenib and sunitinib by in vitro cytotoxicity assays. Figures 1A and 1B show the dose dependent inhibition of AT/RT cell growth by these agents. From these data, IC50 values were calculated and presented in Table 2. IC50 values for each cell line ranged from 2.8 to 3.6 µM for sorafenib and 3.2 to 3.7 µM for sunitinib. As a means to further support the targeted inhibition of receptor pathways by sorafenib and sunitinib, the expression of proteins targeted by these inhibitors was determined by Western blot analysis. It was found that all three AT/RT cell lines expressed receptor tyrosine kinases c-Kit, PDGF-Rβ, VEGFR2 and Flt-3, as well as the intracellular targets of sorafenib, c-Raf and p38α (Figure 2).

Bottom Line: The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination.Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied.In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Pre-clinical and Drug Discovery Studies, Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) and Division of Pediatric Oncology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, T3B 6A8, Canada. anarendr@ucalgary.ca.

ABSTRACT

Background: Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT) constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines.

Results: AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination.

Conclusions: In addition to previously described involvement of insulin like growth factor (IGF) family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

No MeSH data available.


Related in: MedlinePlus