STI571 sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner

Abstract

Previously, we demonstrated that Abl kinases are highly active in invasive breast cancer cell lines, and contribute to survival in response to nutrient deprivation, invasion and proliferation. To determine whether an Abl kinase inhibitor, STI571 (Gleevec; imatinib mesylate) sensitizes breast cancer cells to chemotherapeutic agents, we treated three breast cancer cell lines (BT-549, MDA-MB-231, and MDA-MB-468) that have active Abl kinases, with STI571 in combination with several conventional chemotherapeutic drugs frequently used to treat breast cancer, and assessed the effect on cell viability, proliferation, and apoptosis. We found that STI571 had synergistic effects with cisplatin in BT-549 and to some extent in MDA-MB-468 cells, STI571 synergized with camptothecin using an alternate dosing regimen in MDA-MB-231 cells, and STI571 synergistically sensitized MDA-MB-468 cells to paclitaxel and to high doses of 5-fluorouracil. Significantly, STI571 increased the ability of cisplatin to inhibit constitutive activation of PI3K/Akt, synergized with camptothecin to increase the stability of IκB in MDA-MB-231 cells, and in MDA-MB-468 cells, camptothecin and 5-fluorouracil inhibited STI571-dependent activation of STAT3. In other cell line/drug combinations, STI571 had additive or antagonistic effects, indicating that the ability of STI571 to sensitize breast cancer cells to chemotherapeutic agents is cell type-dependent. Significantly, unlike cisplatin, paclitaxel, and camptothecin, mechloroethamine was strongly antagonistic to STI571, and the effect was not cell line-dependent. Taken together, these data indicate that the cellular milieu governs the response of breast cancer cells to STI571/chemotherapeutic combination regimens, which suggests that treatment with these combinations requires individualization.

Arctigenin enhances chemosensitivity of cancer cells to cisplatin through inhibition of the STAT3 signaling pathway

“…Some reports have shown that the inhibition of STAT3 could sensitize tumor cells to cisplatin-induced cell death [Sims et al, 2009;Liu et al, 2010;Yilmaz et al, 2010]. Therefore, we postulate that arctigenin may promote chemosensitivity of tumor cells to cisplatin through inhibition of STAT3 activity.…”

Activation of Abl Family Kinases in Solid Tumors

“…83 , and active c-Abl was localized in the cytoplasm, similar to BCRAbl and v-Abl. 84,85 Significantly, c-Abl/ Arg activities (assessed by phosphorylation of substrates, Crk/CrkL) were dramatically elevated in primary melanomas relative to benign nevi or normal skin. 83,79 We showed that constitutively active IGF-1R, Her-2, EGFR, and/or SFKs contributed to c-Abl/Arg activation in melanoma and breast cancer lines, ruling out mutation as the method of activation and uncovering a novel activation mechanism in solid tumors (Fig.…”

Systemic Therapy Options for Unresectable and Metastatic Chordomas

“…The reason for increased efficacy of imatinib in combination with cisplatin in chordoma is not clear yet. However, there is increasing preclinical evidence in favor of a synergic activity of these two agents in other cancers and, in particular, that imatinib can sensitize tumor cells to cisplatin [90][91][92][93], at least in some tumors. These data are somehow encouraging and surely deserve further investigation.…”