APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice

Abstract

Platelets contribute to the development of metastasis, the most common cause of mortality in cancer patients, but the precise role that anti-platelet drugs play in cancer treatment is not defined. Metastatic tumor cells can produce platelet aIIbb3 activators, such as ADP and thromboxane A2 (TXA2). Inhibitors of platelet b3 integrins decrease bone metastases in mice but are associated with significant bleeding. We examined the role of a novel soluble apyrase/ ADPase, APT102, and an inhibitor of TXA2 synthesis, acetylsalicylic acid (aspirin or ASA), in mouse models of experimental bone metastases. We found that treatment with ASA and APT102 in combination (ASA + APT102), but not either drug alone, significantly decreased breast cancer and melanoma bone metastases in mice with fewer bleeding complications than observed with aIIbb3 inhibition. ASA + APT102 diminished tumor cell induced platelet aggregation but did not directly alter tumor cell viability. Notably, APT102 + ASA treatment did not affect initial tumor cell distribution and similar results were observed in b3−/− mice. These results show that treatment with ASA + APT102 decreases bone metastases without significant bleeding complications. Anti-platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases.

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

“…Interestingly, a population-based epidemiological study reported that the use of platelet inhibitors aspirin and dipyridamole was associated with increased risk of osteoporotic fractures, but this association was not observed with clopidogrel (73). Clinical studies evaluating the effects on bone in patients receiving clopidogrel or trials of clopidogrel in patients with excessive bone resorption are warranted to determine whether clopidogrel or other novel ADP and P2RY12-targeted therapies (11,67,74) could have a role as in the treatment of disease states characterized by excessive bone resorption. We propose that P2RY12 targeting would likely only have effects on bone during localized increases in extracellular ADP that can occur during tissue damage, inflammation, and cancer, with little effects on normal systemic bone turnover.…”

“…It has been reported that purinergic signaling can modulate platelet function, inflammation, and pathologic angiogenesis, which could modulate bone cell function in certain disease states (2,22,36,(65)(66)(67)(68). Recent preclinical data is conflicting regarding the role of clopidogrel in inflammation both dependently and independently of its effects on platelets (36,68).…”

Metastasis: new functional implications of platelets and megakaryocytes

“…Weilbaecher and colleagues investigated the effect of the soluble ADPase APT102 administered in combination with an inhibitor of TXA2 synthesis (acetylsalicylic acid/aspirin). 58 Although ATP102 and aspirin treatment did not affect primary tumor growth, the combined treatment significantly attenuated the extent of melanoma and breast cancer bone metastasis in mice. 58 …”

“…58 Although ATP102 and aspirin treatment did not affect primary tumor growth, the combined treatment significantly attenuated the extent of melanoma and breast cancer bone metastasis in mice. 58 …”

Purinergic signalling in the musculoskeletal system

“…Early work also highlighted that ATP was useful for purging residual tumour cells in autologous bone marrow transplantation [451]. Furthermore, APT102, a novel form of human apyrase/ADPase, works together with aspirin to disrupt bone metastasis in mice [452]. It is conceivable that ATP released from tumour cells could further stimulate osteoclast formation and activity [12], thus contributing to the so-called vicious cycle of bone destruction that commonly occurs around tumour metastases.…”