Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer

Abstract

Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline-and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

Percutaneous Doxycycline Treatment of Aneurysmal Bone Cysts With Low Recurrence Rate: A Preliminary Report

“…Furthermore, the lack of need for posttreatment physical rehabilitation (once pathologic fractures heal) offers patients greater mobility and maintenance of normal activities of daily living (recreational and work activity within limits set by the patient's orthopaedic surgeon) during the therapeutic regimen. Although the exact mechanism of regression is not known, pathology results in three patients not completing the full protocol of percutaneous treatment suggest direct cytotoxic action on the mesenchymal tumoral ABC component in addition to known metabolic therapeutic targets of doxycycline that inhibit VEGF, MMP, and osteoclast function [4,5,7,12,13,15,18,19,24,27,43].…”

“…In addition to a radiographic demonstration of tumor involution and bony healing, a pathologic analysis of three operative tissue specimens at the authors' institution, after percutaneous doxycycline treatment, documented the direct cytotoxic effect of doxycycline on the mesenchymal ABC cells. Beyond simple cytotoxicity, doxycycline is antiangiogenic [18,37], a potent inhibitor of MMP [12,13,27], an inhibitor of osteoclastic activity [12,13], induces apoptosis in osteoclasts, and promotes osteoblastic activity [4,7,12,13,15,19]. These multiple sites of action serve well to target the neoplastic cell of an ABC, destructive osteoclasts, tumor vascularity ingrowth, and support osteoblastic healing after tumor ablation.…”

“…In bone and soft tissue malignancy cell cultures, doxycycline demonstrates antitumoral properties with inhibition of MMP and angiogenesis [12,13,15], inhibition of osteoclastic function, and induction of osteoclastic apoptosis [12,13,15,19]. Doxycycline enhances osteoblastic healing of bone defects in dogs [8].…”

Zoledronic acid use in cancer patients

“…31 In a murine model of human BC, ZOL alone reduced total tumor burden by 43% compared with placebo; moreover, ZOL plus doxycycline more effectively reduced bone tumor burden compared with doxycycline alone. 22 It is noteworthy that sequential exposure to doxorubicin (2 mg/kg) followed 24 hours later by ZOL (100 lg/kg) decreased intraosseous tumor burden in bone and increased rates of cancer cell apoptosis more than either agent alone, both agents administered simultaneously, or ZOL administered before doxorubicin. 28 Synergistic effects also have been demonstrated in the lung, prostate, and MM settings.…”

“…21 Bisphosphonates also have demonstrated synergistic cytotoxic or cytostatic effects when administered in combination with chemotherapy agents. 17,[22][23][24][25][26][27][28][29][30][31][32][33] In human primary BC cells, concomitant exposure to ibandronate or ZOL plus cyclophosphamide combined with methotrexate and 5-fluorouracil or epirubicin combined with cyclophosphamide, paclitaxel, or docetaxel enhanced the cytostatic effects compared with chemotherapy alone. 31 In a murine model of human BC, ZOL alone reduced total tumor burden by 43% compared with placebo; moreover, ZOL plus doxycycline more effectively reduced bone tumor burden compared with doxycycline alone.…”