Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage-independent growth assays and spheroid-forming capacity, which was determined with ovarian cancer cell lines as well as primary ovarian cancers. Of 12 cell lines with increased anchorage-independent growth, 8 formed spheroids under serum-free culture conditions. Spheroids showed reduced proliferation (P < 0.0001) and Ki-67 immunostaining (8% vs. 87%) relative to monolayer cells. Spheroid formation was associated with increased expression of mitochondrial pathway genes (P ≤ 0.001) from Affymetrix HT U133A gene expression data. UCN-01, a kinase inhibitor/mitochondrial uncoupler that has been shown to lead to Puma-induced mitochondrial apoptosis as well as ATP synthase inhibitor oligomycin, demonstrated effectiveness against spheroids, whereas spheroids were refractory to cisplatin and paclitaxel. By live in vivo imaging, ovarian cancer xenograft tumors were reduced after primary treatment with carboplatin. Continued treatment with carboplatin was accompanied by an increase in tumor signal, whereas there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or oltipraz. Taken together, our findings suggest that genes involved in mitochondrial function in spheroids may be an important therapeutic target in preventing disease recurrence.

中文翻译：

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在体外和体内铂耐药小鼠模型中靶向休眠卵巢癌细胞


球状体表现出耐药性和缓慢增殖，表明与癌症复发有关。蛋白激酶 C 抑制剂 UCN-01（7-羟基星形孢菌素）对缓慢增殖和/或静止的卵巢癌细胞表现出更高的功效。在这项研究中，使用不依赖贴壁的生长测定和球状体形成能力来评估致瘤潜力，这是用卵巢癌细胞系以及原发性卵巢癌测定的。在 12 个贴壁依赖性生长增加的细胞系中，有 8 个在无血清培养条件下形成球状体。相对于单层细胞，球状体的增殖 (P < 0.0001) 和 Ki-67 免疫染色 (8% vs. 87%) 有所减少。根据 Affymetrix HT U133A 基因表达数据，球体形成与线粒体途径基因表达增加相关 (P ≤ 0.001)。 UCN-01 是一种激酶抑制剂/线粒体解偶联剂，已被证明可导致 Puma 诱导的线粒体凋亡，以及 ATP 合成酶抑制剂寡霉素，证明对球状体有效，而球状体对顺铂和紫杉醇无效。通过活体成像，卵巢癌异种移植肿瘤在卡铂初步治疗后有所减少。继续用卡铂治疗伴随着肿瘤信号的增加，而随后用UCN-01或奥替普拉治疗时观察到肿瘤信号很少或没有增加。综上所述，我们的研究结果表明，球体中参与线粒体功能的基因可能是预防疾病复发的重要治疗靶点。