Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Sci Rep. 2021 Apr 23;11(1):8844. doi: 10.1038/s41598-021-87734-6.
A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APC mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APC mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP cancer cell lines.
一种人源家族性腺瘤性息肉病的小鼠模型对 5'-甲基硫代腺苷磷酸化酶（MTAP）的药理抑制反应良好。Methylthio-DADMe-Immucillin-A（MTDIA）是一种可口服的 MTAP 过渡态类似物抑制剂。5'-甲基硫代腺苷（MTA）是 MTAP 的底物，在多胺合成中形成，并通过补救途径由 MTAP 回收至 S-腺苷-L-蛋氨酸（SAM）。MTDIA 治疗会导致 MTA 的积累，从而抑制免疫缺陷小鼠模型中人头颈部（FaDu）和肺部（H359、A549）癌症的生长。我们研究了口服 MTDIA 作为免疫活性 APC 小鼠（人家族性腺瘤性息肉病的一种小鼠模型）肠道腺瘤的抗癌治疗的疗效。MTDIA 治疗可使 APC 小鼠的肿瘤体积减小，导致贫血明显改善，小鼠寿命延长一倍。与对照小鼠相比，经处理的小鼠的代谢组学分析显示多胺、蛋氨酸、SAM 或 ATP 水平没有变化，但表明 MTA（MTAP 底物）增加。在培养中生成 MTDIA 抗性细胞系表明甲硫氨酸腺苷转移酶（MAT2A）基因座扩增了四倍，并且该酶表达增加。MAT2A 是 MTAP 作用的下游产物，催化合成用于甲基化反应的 SAM。用 MTDIA 处理的小鼠肠道组织的免疫组织化学分析表明对称二甲基精氨酸（PRMT5 催化的修饰物）减少。MTDIA 的抗癌作用表明，细胞内 MTA 的增加抑制了 PRMT5 介导的甲基化，从而导致肿瘤生长减弱。MTDIA 的口服给药作为单一疗法具有延迟家族性腺瘤性息肉病（FAP）中结直肠癌的发生和进展以及 FAP 患者结肠切除术后残留十二指肠肿瘤的潜力。MTDIA 导致 MTAP 的生理性失活，并且与 MAT2A 或 PRMT5 的抑制剂联合使用可能也具有疗效，这在 MTAP 癌细胞系中是已知的合成致死相互作用。
