Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models

Abstract

BackgroundRecent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models.Principal FindingsWe report that chemotherapeutic drug doxorubicin activates TGFβ signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TβR1-KI was administered in combination with doxorubicin.ConclusionsThese observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.

Targeting TGF-β Signaling for Therapeutic Gain

“…Several papers have shown the preclinical efficacy of targeting tumors with combinations of cytotoxic drugs and TGF-b blockade. Synergism between the DNA intercalating agent, doxorubicin, and TGF-b inhibition has been shown to suppress breast cancer growth and metastasis in a preclinical model (Bandyopadhyay et al 2010), and TGFb inhibitors potentiate the cytotoxic effects of the alkylating agent, melphalan, and the corticosteroid, dexamethasone, in a model of multiple myeloma (Takeuchi et al 2010). Exposure of multiple myeloma cells to differentiated versus immature MC3T3-E1 pro-osteoblastic cells in cell culture potentiates chemotherapy-induced myeloma cell death.…”

Epithelial-mesenchymal transition and drug resistance in breast cancer (Review)

“…A recent study indicated that adverse activation of TGF-β pathway by chemotherapeutics in the breast cancer cells or elevated TgF-β levels in tumor microenvironment might lead to EMT and generation of cancer stem cells, resulting in the resistance to chemotherapy (40). The evidence found cis-platinum treatment of MDA-MB-231 breast cancer cells increased both TgF-β mRNA levels and the secretion of active TGF-β, which enhanced growth arrest that facilitated repair of damage, thus rendering these cells resistant to cis-platinum killing (41).…”

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

“…For an older chemotherapy agent such as doxorubicin with many side effects, a higher dose might be used in some breast cancer situation and prevent its metastasis than currently possible with IV infusion. A combination of STID100 with systemic chemotherapy agents is also an attractive breast conservation option for some aggressive cancers post-surgery resection [33] [34]. Given the simplicity of the STID construction, STIDs containing new agents such as gemcitabine, Taxol, or even immunotherapy agents are theoretically possible with even better benefits and risk differentiation.…”