Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Health Services, Santa Monica, CA 90404, USA.
Sci Signal. 2024 Nov 19;17(863):eado8303. doi: 10.1126/scisignal.ado8303.
High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids but had negligible cytotoxicity in immortalized, nontumorigenic fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface epithelial cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in subcutaneous and intraperitoneal xenograft models. These antitumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.
高级别浆液性卵巢癌（HGSOC）是女性中致死率最高的癌症之一，其生存率低、缺乏早期检测生物标志物、复发率高、治疗选择有限。 forskolin 是环磷酸腺苷信号的激活剂，具有多种抗癌活性，包括针对 HGSOC，但在体内的应用有限。其水溶性衍生物 colforsin daropate 与 forskolin 具有相同的作用机制，用于治疗急性心力衰竭。在这里，我们研究了 colforsin daropate 作为治疗 HGSOC 的潜力。我们发现 colforsin daropate 诱导培养的 HGSOC 细胞和球体中的细胞周期停滞和细胞凋亡，但对永生化、非肿瘤性输卵管分泌细胞和卵巢表面上皮细胞几乎没有细胞毒性。colforsin daropate 还可防止 HGSOC 细胞在培养物中侵袭卵巢表面上皮细胞层。在体内，colforsin daropate 减少肿瘤生长，与顺铂（卵巢癌治疗中的标准化疗药物）协同作用，并改善皮下和腹腔异种移植模型中的宿主存活率。colforsin daropate 的这些抗肿瘤作用部分是通过降低癌蛋白 c-MYC 的丰度和转录活性介导的，c-MYC 在 HGSOC 中通常增加。我们的研究结果表明，colforsin daropate 可能是一种有前途的治疗方法，可与常规疗法联合用于治疗 HGSOC。
