Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
Department of Women's Health, Geisinger Medical Center, Danville, PA, USA.
BMC Cancer. 2020 Apr 3;20(1):273. doi: 10.1186/s12885-020-06752-1.
Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells.
The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array.
Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment.
Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.
上皮性卵巢癌（EOC）占恶性卵巢肿瘤的大多数。联合化疗似乎是卵巢癌（OVCA）患者克服耐药性的一种有前途的策略。在这项体外研究中，我们研究了单独使用维替泊芬（VP）以及与顺铂（CDDP）、卡铂（CP）和紫杉醇（Taxol）联合使用治疗的疗效。本研究的主要目的是确定 VP 与 CDDP/CP/Taxol 之间相互作用的性质，并了解 VP 在 OVCA 细胞中的作用机制。
在 CDDP 敏感（COV504、OV-90）和 CDDP 耐药（A2780Cis）细胞系中，测定 VP 对细胞增殖、细胞毒性、侵袭和克隆形成能力的影响。分别用 MTT 法和细胞活力蓝检测药物单独或联合使用的细胞毒性作用。用基质胶侵袭试验和克隆形成试验研究药物对代谢功能的影响。用免疫印迹分析研究 YAP 和细胞周期基因的变化。用细胞因子阵列分析因药物处理而导致的细胞因子变化。
VP 治疗抑制了 OVCA 细胞的增殖、侵袭和增加了细胞毒性。我们观察到，VP 即使在较低剂量下也能使 CDDP 耐药细胞增敏。当以恒定或非恒定比例加入时，VP 与 CDDP/CP/Taxol 联合产生协同作用。细胞因子阵列鉴定出 OVCA 细胞中因 VP 处理而上调的细胞因子。
无论是在 CDDP 耐药细胞系还是 CDDP 敏感细胞系中，VP 都能更有效地抑制细胞增殖并诱导细胞毒性。我们的结果表明，VP 与 CDDP 或 CP 或 Taxol 的新组合可能是增强 OVCA 化疗敏感性的一种有吸引力的治疗策略。VP 以较低剂量有效增敏 CDDP 耐药细胞的事实，最终可能导致为治疗 OVCA 患者开发创新的联合治疗。
