Nunes Mariana, Ricardo Sara
Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal.
Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.
Pharmaceuticals (Basel). 2024 Dec 25;18(1):14. doi: 10.3390/ph18010014.
Chemoresistance is a major obstacle in high-grade serous carcinoma (HGSC) treatment. Although many patients initially respond to chemotherapy, the majority of them relapse due to Carboplatin and Paclitaxel resistance. Drug repurposing has surfaced as a potentially effective strategy that works synergically with standard chemotherapy to bypass chemoresistance. In a prior study, using 2D cultures and two HGSC chemoresistant cell lines, it was demonstrated that combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin resulted in the most notable synergy. Acknowledging that 2D culture systems are limited in reflecting the tumor architecture, 3D cultures were generated to provide insights on treatment efficacy tests in more complex models.
We aimed to investigate whether combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin offers therapeutic benefits in a Cultrex-based 3D model.
Here, the cytotoxicity of Carboplatin and Paclitaxel, both alone and in combination with Pitavastatin or Ivermectin, were analyzed on two chemoresistant tumor cell lines, OVCAR8 and OVCAR8 PTX R C, in 3D cultures. Cellular viability was assessed using CellTiter-Glo Luminescent assays. Also, it explored synergistic interactions using zero interaction potency, Loewe, Bliss independence, and High-single agent reference models.
Our research indicates combining chemotherapeutic drugs with Pitavastatin or Ivermectin yields significantly more cytotoxic effects than chemotherapy alone. For all the combinations tested, at least one model indicated an additive effect; however, only the combination of Paclitaxel and Ivermectin consistently demonstrated an additive effect across all chemoresistant cell lines cultured in 3D models, as well as in all four synergy reference models used to assess drug interactions.
Combining Paclitaxel with Ivermectin has the highest cytotoxic and the strongest additive effect for both chemoresistant cell lines compared to Paclitaxel alone.
化疗耐药是高级别浆液性癌（HGSC）治疗中的主要障碍。尽管许多患者最初对化疗有反应，但大多数人会因对卡铂和紫杉醇耐药而复发。药物重新利用已成为一种潜在有效的策略，可与标准化疗协同作用以绕过化疗耐药。在先前的一项研究中，使用二维培养和两种HGSC化疗耐药细胞系，证明将卡铂或紫杉醇与匹伐他汀或伊维菌素联合使用可产生最显著的协同作用。认识到二维培养系统在反映肿瘤结构方面存在局限性，因此生成了三维培养物，以便在更复杂的模型中对治疗效果测试提供见解。
我们旨在研究在基于Cultrex的三维模型中，将卡铂或紫杉醇与匹伐他汀或伊维菌素联合使用是否具有治疗益处。
在此，分析了卡铂和紫杉醇单独使用以及与匹伐他汀或伊维菌素联合使用时，对三维培养中的两种化疗耐药肿瘤细胞系OVCAR8和OVCAR8 PTX R C的细胞毒性。使用CellTiter-Glo发光测定法评估细胞活力。此外，还使用零相互作用效力、洛氏、布利斯独立性和高单一药物参考模型探索了协同相互作用。
我们的研究表明，与单独化疗相比，将化疗药物与匹伐他汀或伊维菌素联合使用产生的细胞毒性作用显著更强。对于所有测试的组合，至少有一个模型显示出相加效应；然而，只有紫杉醇和伊维菌素的组合在三维模型中培养的所有化疗耐药细胞系以及用于评估药物相互作用的所有四种协同参考模型中始终显示出相加效应。
与单独使用紫杉醇相比，将紫杉醇与伊维菌素联合使用对两种化疗耐药细胞系具有最高的细胞毒性和最强的相加效应。
