https://blog.superhyydl.org/tags/%E8%8D%AF%E7%89%A9%E9%87%8D%E5%AE%9A%E4%BD%8D/Recent content in 药物重定位 on Superhyydl's BlogHugozh-cnTue, 01 Sep 2026 00:00:00 +0000https://blog.superhyydl.org/reading/canagliflozin-is-a-novel-androgen-receptor-pathway/Tue, 01 Sep 2026 00:00:00 +0000https://blog.superhyydl.org/reading/canagliflozin-is-a-novel-androgen-receptor-pathway/<h2 id="一句话亮点">一句话亮点</h2> <p>降糖药卡格列净（Canagliflozin）不仅能结合AR配体结合域（LBD）阻断信号，还能通过下调HSP70、促进泛素化，降解全长AR和截短变异体AR-V7——后者正是导致临床ARPI耐药的头号罪犯。</p> <h2 id="背景痛点">背景/痛点</h2> <p>目前前列腺癌治疗的大逻辑是雄激素剥夺（ADT）+二代AR通路抑制剂（ARPIs，如恩杂鲁胺、阿帕他胺）。这套组合拳确实延长了生存期，但两个现实问题始终摆在那：一是药物副作用大（骨质疏松、心血管事件、性欲丧失），二是迟早耐药，尤其AR-V7阳性的患者，恩杂鲁胺基本等于白用。</p> <p>AR-V7这种截短变异体缺了配体结合域（LBD），所以靶向LBD的传统ARPI根本拿它没办法。过去十来年大家都在找能同时降解AR-FL和AR-Vs的分子，PROTAC这类策略很热闹，但至今没有一个走到临床。那作者就琢磨了：与其从头设计一个新分子，不如看看已有药物里有没有能&quot;兼职&quot;干这活的？</p> <p>他们之前已经发现卡格列净能抑制前列腺癌生长、改变基因表达谱，而且被调得最明显的恰恰是AR信号通路的基因。所以这篇文章的核心假说就这么来了：卡格列净可能是一个被忽略的、藏身在降糖药里的新型ARPI。</p> <h2 id="推理链分步拆解">推理链分步拆解</h2> <h3 id="第一步先看效果卡格列净能抑瘤而且有独特优势">第一步：先看效果——卡格列净能抑瘤，而且有独特优势</h3> <p>作者首先要确认的是，卡格列净在体外和体内的抗肿瘤效果到底怎么样，跟现有SGLT2抑制剂和二代ARPI比有没有竞争力。他们在LNCaP（CSPC）和22RV1（CRPC）两种细胞系上做了增殖和克隆形成实验。结果挺有意思的：同属SGLT2i的达格列净几乎没效果，而卡格列净的抑制能力跟阿帕他胺、达罗他胺相当，在22RV1里的IC50还优于恩杂鲁胺（恩杂鲁胺在22RV1里IC50 &gt; 100 μM，基本等于无效）。</p> <p>在22RV1荷瘤小鼠模型里，7天短期给药肿瘤体积就缩了65%，长期给药生存期延长了10天（对照组18天 vs 卡格列净组28天）。体重没掉，只是喝水多了、尿多了——这是SGLT2抑制剂在啮齿动物里的经典表现，说明给药是有效的。</p> <p>@方法论点评：这里做了一个很重要的对照——达格列净无效，说明卡格列净的效果不是SGLT2抑制这个&quot;本职功能&quot;带来的，而是&quot;脱靶&quot;的。这为后续找AR这个新靶点铺了路。体内实验设计也严谨：先做短期（看分子标志物变化）再做长期（看生存获益），两套数据互相印证。</p> <p><img alt="Fig. 1：Canagliflozin suppresses cell proliferation, clonogenic survival, and tumor growth in vitro and in vivo. LNCaP and 22RV1 cells were treated with clinically achievable concentrations of SGLT2is, canagliflozin and dapagliflozin (0–30 μM), or antiandrogens, enzalutamide, apalutamide, and darolutamide (0–10 μM), and (A-B) cell proliferation or (C) clonogenic survival was assessed. (D) Schematic of the in vivo treatment regimen for NRG mice bearing 22RV1 xenografts, showing short-term (Exp. #1) and long-term survival (Exp. #2) endpoints (created with BioRender.com). (E–F) In vivo tumor growth kinetics for (E) Exp. #1 (N = 6–7) and (F) Exp. #2 (N = 5). Tumor volumes are shown as mean ± SD for Exp. #1 and mean ± SD for Exp. #2. Tumor growth curves in panel E were analyzed using mixed-effects modeling with FDR correction, while panel F was analyzed using a mixed-effects model (REML) for repeated measures. (G) Kaplan–Meier analysis of time to tumor endpoint for Exp. #2. Event was defined as tumor volume ≥2000 mm3. Statistical significance was determined using the log-rank (Mantel–Cox) test. (H–J) Mouse body weight at endpoint (H), diet intake (I), and water intake (J) for Exp. #1. (K–M) Average body weight (K), diet intake (L), and water intake (M) for Exp. #2. (N) Phosphorylated histone H3 (P-HH3 (Ser10)) immunohistochemistry with digitally overlaid identification of P-HH3–positive nuclei for Exp. #1. For data analysis, cells and tumors were used with at least N ≥3 biological replicates. Statistical significance for panels H–M was determined using a two-tailed unpaired Student&rsquo;s t-test, while other comparisons were analyzed using one- or two-way ANOVA with Tukey&rsquo;s post-hoc multiple comparisons test. Data are presented as mean ± SEM, except for in vivo panels E–F and K–M, which are shown as mean ± SD. Statistical significance is indicated as P &lt; 0.05, P &lt; 0.01, P &lt; 0.001, P &lt; 0.0001." loading="lazy" src="https://blog.superhyydl.org/images/reading/canagliflozin-is-a-novel-androgen-receptor-pathway/figure-01.png"></p>