Doxorubicin-Mediated Bone Loss in Breast Cancer Bone Metastases Is Driven by an Interplay between Oxidative Stress and Induction of TGFβ

Abstract

Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFβ antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Cancer treatment-induced bone loss (CTIBL): Pathogenesis and clinical implications

“…Moreover, in a preclinical murine model of breast cancer, doxorubicin induced a significant decrease in TBV and increased serum markers of bone resorption. These phenomena were also observed in non-tumor bearing mice, suggesting that the bone health impairment was tumor independent [45].…”

“…Besides its cardiotoxic and myelosuppressive effects, doxorubicin may compromise the bone health by increasing OC differentiation and reducing fibroblast and OB forming units that derive from BMSCs, as described in vitro by Rana et al [45]. These effects are mediated by oxidative stress, confirmed by superoxide dismutase downregulation, and partially abrogated by an anti-TGFb antibody, suggesting that there is also a hyperactivation of the TGFb pathway in doxorubicin-treated cells.…”

Cancer‐ and Chemotherapy‐Induced Musculoskeletal Degradation

“…In particular, preclinical studies of breast cancer bone metastases have shed much light on this topic. Doxorubicin and carboplatin chemotherapies have been used to study musculoskeletal changes and have revealed that these agents alone cause significant reduction in bone volume . The combination therapy Folfiri (5‐fluorouracil, leucovorin, and irinotecan) also causes reduced bone volume …”

Chalcone derivative cytotoxicity activity against MCF-7 human breast cancer cell QSAR study

“…Although there are many therapeutic strategies, more than one million new cases of breast cancer are diagnosed every year [3]. Some of the main problems in the treatment of cancer are high cytotoxicity and drug resistance, and no clinically active substances are known to act selectively on tumor cells.…”