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Published on: September 26, 2016
APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice
Ozge Uluçkan1, Mark C Eagleton, Desiree H Floyd
1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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 alphaIIb beta3 activators, such as ADP and thromboxane A(2) (TXA(2)). Inhibitors of platelet beta3 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 TXA(2) 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 alphaIIb beta3 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 beta3-/- 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.
Insights
Combining aspirin (ASA) and APT102 significantly reduced bone metastases in mice by inhibiting platelet aggregation, offering a potential therapy with fewer bleeding risks than other anti-platelet drugs.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Metastasis, a primary cause of cancer mortality, involves platelets.
- Tumor cells activate platelets via ADP and thromboxane A(2) (TXA(2)).
- Existing anti-platelet therapies targeting alphaIIb beta3 integrins reduce bone metastases but cause bleeding.
Purpose of the Study:
- To evaluate the efficacy of a novel soluble apyrase/ADPase (APT102) and acetylsalicylic acid (aspirin, ASA) combination in preventing bone metastases.
- To assess the safety profile, specifically bleeding complications, of this combined anti-platelet therapy.
Main Methods:
- Utilized mouse models of experimental bone metastases (breast cancer and melanoma).
- Administered a combination of APT102 and ASA, comparing it to individual drug treatments and alphaIIb beta3 inhibition.
- Assessed metastasis reduction, platelet aggregation, tumor cell viability, and bleeding complications.
Main Results:
- The combination of ASA + APT102 significantly decreased bone metastases in mice.
- This combination therapy showed fewer bleeding complications compared to alphaIIb beta3 inhibition.
- ASA + APT102 reduced tumor cell-induced platelet aggregation without affecting tumor cell viability or initial distribution.
Conclusions:
- Combined treatment with aspirin and APT102 effectively reduces bone metastases with an improved safety profile.
- This therapeutic strategy warrants further investigation as a potential treatment for preventing bone metastasis.
- ASA + APT102 serves as a valuable experimental tool for understanding platelet roles in metastasis.
