Molecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
Immunology Section, Department of Medicine, University of Udine, Udine, Italy.
Front Immunol. 2021 Mar 2;12:622001. doi: 10.3389/fimmu.2021.622001. eCollection 2021.
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 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. , 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.
去势抵抗性前列腺癌（CRPC）的一个相关部分在抵抗雄激素剥夺和/或雄激素受体通路抑制剂的情况下演变为致命的神经内分泌（NEPC）肿瘤。因此，需要针对 CRPC 和 NEPC 都有效的药物。我们之前描述了肥大细胞（MCs）在前列腺癌中的双重作用，既能促进腺癌，也能抑制 NEPC。这一发现表明，一种既能针对 MC 又能针对 NEPC 细胞的分子可能对前列腺癌有效。我们使用药物再利用方法，发现抗癫痫药物左乙拉西坦是一种有潜力的候选药物。我们发现左乙拉西坦的蛋白靶标 SV2A 在 NEPC 细胞和浸润前列腺腺癌的 MC 中高度表达，而在腺癌细胞中则低或可忽略不计。此外，左乙拉西坦抑制了 NEPC 细胞的增殖和 MC 的脱颗粒。在皮下肿瘤荷瘤小鼠中，左乙拉西坦对 NEPC 和腺癌均有部分活性，后者的作用是由于 MC 释放 MMP9 受到抑制。值得注意的是，在接受手术去势以模拟雄激素剥夺治疗的转基因小鼠前列腺癌（TRAMP）小鼠中，左乙拉西坦减少了高级别前列腺上皮内瘤变、腺癌和 NEPC 的发生和频率，从而增加了仅显示肿瘤消退迹象的治愈小鼠数量。我们的结果表明，左乙拉西坦可以在去势后直接抑制 NEPC 的发展，并且可以通过抑制某些 MC 功能来阻断腺癌的进展。这些发现为进一步测试左乙拉西坦治疗前列腺癌或 MC 介导的疾病提供了可能性。
