Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Protects Against Adriamycin and Cyclophosphamide Chemotherapy-Induced Bone Marrow Damage in Female Rats

Abstract

Although bone marrow and bone toxicities have been reported in breast cancer survivors, preventative strategies are yet to be developed. Clinical studies suggest consumption of long chain omega-3 polyunsaturated fatty acids (LCn3PUFA) can attenuate age-related bone loss, and recent animal studies also revealed benefits of LCn3PUFA in alleviating bone marrow and bone toxicities associated with methotrexate chemotherapy. Using a female rat model for one of the most commonly used anthracycline-containing breast cancer chemotherapy regimens (adriamycin + cyclophosphamide) (AC) chemotherapy, this study investigated potential effects of daily LCn3PUFA consumption in preserving bone marrow and bone microenvironment during chemotherapy. AC treatment for four cycles significantly reduced bone marrow cellularity and increased marrow adipocyte contents. It increased trabecular bone separation but no obvious changes in bone volume or bone cell densities. LCn3PUFA supplementation (375 mg/100 g/day) attenuated AC-induced bone marrow cell depletion and marrow adiposity. It also partially attenuated AC-induced increases in trabecular bone separation and the cell sizes and nuclear numbers of osteoclasts formed ex vivo from bone marrow cells isolated from AC-treated rats. This study suggests that LCn3PUFA supplementation may have beneficial effects in preventing bone marrow damage and partially protecting the bone during AC cancer chemotherapy.

Comparative Histological Study on the Protective Effect of Folinic Acid versus Fish Oil on the Growing Bone of Methotrexate-Treated Young Rats

“…Metaphyseal bone sections of MTX and FO-treated group showed marked improvement in the histological architecture of primary and secondary spongiosa trabeculae with BM cavities occupied mostly by developing hemopoietic stem cells. These findings were in agreement with [24] who reported that daily omega-3 PUFAs supplementation during MTX chemotherapy could enhance osteogenic differentiation through induction of osteogenesis factors and also inhibiting expression of osteoclastogenesis as well as adipogenesis factors.…”

“…It is noteworthy to mention that, BM adipocytes do not just simply fill the marrow spaces, but can act as negative regulators of the BM microenvironment and have direct functions on hematopoietic cells [24] .…”

“…Omega-3 PUFAs have the ability to inhibit osteoclasts formation through their anti-inflammatory properties [33] . Omega-3 PUFAs also promote production of IGF-1 which stimulates growth of bone, thereby helping to attenuate MTX chemotherapy-induced bone loss as well as preserving bone formation in rats [24] .…”

Physiologic and pathologic effects of dietary free fatty acids on cells of the joint

“…In ovariectomized mice, supplementation with omega‐3 PUFAs increased femoral neck BMD and decreased osteoclast number . Furthermore, a diet supplemented with fish oil or omega‐3 PUFAs prevented bone loss during chemotherapy, reduced bone resorption markers, and increased bone density in periodontitis . Additionally, a maternal diet rich in omega‐3 PUFAs was correlated with a downregulation of osteoclastogenesis in offspring (Fig.…”

Hematotoxicity and functional impacts related to chemotherapy with doxorubicin and cyclophosphamide for invasive ductal breast carcinoma: a study in clinical records

“…In this context, doxorubicin, an anthracycline, and cyclophosphamide, an alkylating agent, are often combined and adopted in different protocols. Although effective, especially in advanced tumors, the side effects of this combination on the bone marrow are commonly reported, impairing the hematopoietic function of patients undergoing chemotherapy 3,4 .…”