Background: Nab-paclitaxel, also known as Abraxane®, is paclitaxel formulated in nanoparticles that consist of human albumin encapsulating the hydrophobic drug moiety. This drug has shown numerous advantages including linear pharmacokinetics, significantly higher tumor retention, and increased maximal-tolerated dose due to reduced toxicity. We previously showed that combination of Abraxane and anti-VEGF-A antibody, bevacizumab, is significantly more efficacious in suppression of breast tumor xenografts and metastasis as compared to treatments with each of these drugs alone. We hypothesized that the mechanism underlying the therapeutic success of the combined therapy might include bevacizumab-dependent abrogation of the stress response elicited by paclitaxel in the tumor cells surviving chemotherapy. Materials and Methods: Cultured MDA-MB-231 cells were treated with 0, 2.5, 5, 10, and 30 nM of Abraxane followed by detection of angiogenic (VEGF-A), prosurvival (p42 & p44 kinase, bcl-2) and inflammatory (IL-6, IL-8, and TNF-α) proteins using Western blotting and ELISA. MDA-MB-231 tumors were extracted from mice upon cessation of intravenous (IV) Abraxane therapy (10 to 30 mg/kg, qdx5) followed by Western blot and immunohistochemical analyses. Results: In vitro, Abraxane treatment increased expression of VEGF-A, p42/44 kinase, bcl-2 as well as total and phosphorylated p65 subunit of NF-κB. Treated cells secreted 25- to 30-fold higher concentrations of inflammatory cytokines IL-6, IL-8, and TNF-α into conditioned media as compared with untreated control cells. Likewise, significant increases in bcl-2 and inflammatory cytokines were observed in tumors extracted immediately after paclitaxel therapy in vivo as confirmed by both Western blotting and immunohistochemical analyses. Discussion: These findings suggest that paclitaxel elicits VEGF-A dependent prosurvival and proinflammatory stress responses in tumor cells surviving the cytotoxic therapy. Activation of these pathways suggests that concurrent therapy with VEGF-A neutralizing antibody might significantly improve the efficacy of paclitaxel-based therapies by counteracting the stress responses in the therapy-spared tumor cells.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1032.
Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX