Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma

Abstract

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases.

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…Thus, levetiracetam may inhibit the development of neuroendocrine PC after androgen deprivation therapy and block the progression of adenocarcinoma through the inhibition of mast cells. On the other hand, like valproic acid, it also inhibits HDAC, but this study demonstrated that extremely high doses of levetiracetam are required to cause these effects [ 57 ].…”

Frenemies in the Microenvironment: Harnessing Mast Cells for Cancer Immunotherapy

“…Recently, we discovered a new way to prevent MC degranulation by utilizing the antiepileptic drug levetiracetam [ 86 ], which is administered to avoid and mitigate seizures in patients [ 87 ]. Levetiracetam targets the synaptic vesicle protein 2A (SV2A) [ 88 ]—mainly present in neural and endocrine cells and involved in cell exocytosis [ 89 ]—and we found that this protein is also expressed by prostate cancer-infiltrating MCs [ 86 ]. We demonstrated that levetiracetam can inhibit MC degranulation and, in particular, the release of MMP9, thus restraining the pro-adenocarcinoma activity of MCs in TRAMP mice [ 86 ].…”

“…Levetiracetam targets the synaptic vesicle protein 2A (SV2A) [ 88 ]—mainly present in neural and endocrine cells and involved in cell exocytosis [ 89 ]—and we found that this protein is also expressed by prostate cancer-infiltrating MCs [ 86 ]. We demonstrated that levetiracetam can inhibit MC degranulation and, in particular, the release of MMP9, thus restraining the pro-adenocarcinoma activity of MCs in TRAMP mice [ 86 ]. Furthermore, we also found the expression of SV2A in neuroendocrine prostate cancer and proved that, in this preclinical model, levetiracetam was also able to prevent neuroendocrine differentiation of adenocarcinoma after hormone therapy [ 86 ].…”

Use of Antiepileptic Drugs and Risk of Prostate Cancer: A Nationwide Case-Control Study in Prostate Cancer Data Base Sweden

“…Identification and repurposing of specific drugs such as AED may provide new therapeutic indications for substances with established safety profiles, potentially lower overall development costs, and shorter development timelines [ 3 , 4 ]. In addition to cancer cell cycle arrest, differentiation, and cell death, HDACi also moderates angiogenesis and modifies the immune response.…”