Chemoprevention Activity of Dipyridamole in the MMTV-PyMT Transgenic Mouse Model of Breast Cancer

Abstract

Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter driven polyoma middle T oncoprotein (MMTV-PyMT) metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and microRNA (miRNA) expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChip® or miRNA 2.0 arrays. Real-time quantitative PCR (qPCR) was used to confirm changes in gene expression. Treatment with DPM beginning at the age of four weeks delayed the onset of palpable lesions, delayed tumor progression and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPM’s chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention.

Inhibition of breast cancer cell migration by activation of cAMP signaling

“…These observations, as well as our finding in this study that PDE8A is prominently expressed at the mRNA level in all breast cancer cells and tissues examined, and the recent finding that PDE8A binds to and regulates raf-1 [31], which controls many fundamental biological processes, suggests that PDE8A may provide an excellent novel target for inhibiting breast cancer metastasis. Of note, the nonselective PDE inhibitor, dipyridamole, which in contrast to the nonselective methylxanthine PDE inhibitors, is capable of inhibiting PDE8A, and which we show to significantly inhibit breast cancer cell migration, was recently shown to inhibit breast cancer tumorigenesis and metastasis in animal models [59][60][61], further suggesting that PDE8A may represent an excellent new target for breast cancer treatment.…”

Inhibition of Microbial Beta-Glucuronidase Does Not Prevent Breast Carcinogenesis in the Polyoma Middle T Mouse

“…The published literature of chemoprevention studies using the MMTV-PyMT mouse model [19,22,42] suggests that potential drugs that could have chemoprevention properties have a standardized effect size (SES) that range between 20-80% (0.2 to 0.5). The assumption of our analysis is based on the fact that ~90-100% of the MMTV-PyMT mice at 12-14 weeks develop tumors covering the entire spectrum of histology evaluated [17].…”

“…In this regard, a well-studied mouse model of breast tumor progression, the MMTV-PyMT 634 mice, is endowed with the development of early lesions (hyperplasia/adenoma) that are strongly estrogenreceptor positive, and this was a key driver of our present study [16,17]. This mouse model has been extensively and reproducibly characterized with respect to dietary interventions and tumor progression stages and hormonereceptor status and other biomarkers [16,[18][19][20][21][22][23][24][25]. With respect to our hypothesis, if the intestinal "estrabolome" had significant estrogen metabolic effects, it might be conceivable that the development of early lesions (e.g., hyperplasia/adenoma) might drive lesions forward towards a frank carcinoma due to the availability of recirculating estrogen.…”

Endothelium and cancer metastasis: Perspectives for antimetastatic therapy

“…Another interesting approach studied is based on the agents revealing multiple vascular oriented activities such as dipyridamol, a drug utilized in prophylactics of stroke or pulmonary hypertension. Dipyridamol possessing not only antiplatelet but also vasodilatative potential may contribute to a sustained homeostasis of the blood vessel and as such has been shown to exert antitumor and antimetastatic activity in vivo [104]. Among vascular-targeted drugs that have been studied in regard to their anticancer potential compounds normalizing lipid metabolism should not be omitted.…”