Correction: 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 TGFb in murine pre-clinical models. TGFb 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 TGFb-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-TGFb 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-TGFb antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFb antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas

“…As TGF-β is reported to inhibit the expression of RUNX2 [169], it seems relevant that impairing the TGF-β pathway may have a critical influence on osteoblastic differentiation. This hypothesis was recently verified by Rana et al, who observed that impairing the TGF-β pathway through the use of an anti-TGF-β antibody improves doxorubicin-mediated inhibition of osteoblastic differentiation and increases the frequency of osteoblast colony-forming units [170]. In addition, the anti-osteoblastic-differentiation role of the TGF-β pathway was supported by Maeda et al [171].…”

A Study of the Effects of Doxorubicin-Containing Liposomes on Osteogenesis of 3D Stem Cell Spheroids Derived from Gingiva

“…It was shown that doxorubicin induced decreases of osteoblast survival and differentiation in the previous report [19]. Significant changes were observed from 10 μg/mL groups, so that we used this concentration for experiments in this study.…”

Bone Metastasis Pain, from the Bench to the Bedside

“…Another important factor in bone marrow metastases is oxidative stress: for example, the known chemotherapeutic agent doxorubicin, although helpful as cancer drug, has been shown to cause bone loss due to induction of oxidative stress in osteoclasts in vitro, which causes an increase in their activity. TGF-β also seems to be involved in this process [57]. Consistently, treating neuroblastoma cells in vitro with an antioxidant can impair their growth [58].…”