Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures
Background: 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...
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MDPI AG
2024-12-01
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| author | Mariana Nunes Sara Ricardo |
| author_facet | Mariana Nunes Sara Ricardo |
| author_sort | Mariana Nunes |
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| description | Background: 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. Objectives: We aimed to investigate whether combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin offers therapeutic benefits in a Cultrex-based 3D model. Methods: 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<sup>®</sup> Luminescent assays. Also, it explored synergistic interactions using zero interaction potency, Loewe, Bliss independence, and High-single agent reference models. Results: 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. Conclusions: Combining Paclitaxel with Ivermectin has the highest cytotoxic and the strongest additive effect for both chemoresistant cell lines compared to Paclitaxel alone. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2024-12-01 |
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| series | Pharmaceuticals |
| spelling | doaj-art-61f1bb0fdcda4bb6adeb5d0da1ae88b82025-01-24T13:44:59ZengMDPI AGPharmaceuticals1424-82472024-12-011811410.3390/ph18010014Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell CulturesMariana Nunes0Sara Ricardo1Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, PortugalDifferentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, PortugalBackground: 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. Objectives: We aimed to investigate whether combining Carboplatin or Paclitaxel with Pitavastatin or Ivermectin offers therapeutic benefits in a Cultrex-based 3D model. Methods: 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<sup>®</sup> Luminescent assays. Also, it explored synergistic interactions using zero interaction potency, Loewe, Bliss independence, and High-single agent reference models. Results: 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. Conclusions: Combining Paclitaxel with Ivermectin has the highest cytotoxic and the strongest additive effect for both chemoresistant cell lines compared to Paclitaxel alone.https://www.mdpi.com/1424-8247/18/1/143D cultureschemoresistancedrug repurposinghigh-grade serous carcinomadrug synergism |
| spellingShingle | Mariana Nunes Sara Ricardo Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures Pharmaceuticals 3D cultures chemoresistance drug repurposing high-grade serous carcinoma drug synergism |
| title | Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures |
| title_full | Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures |
| title_fullStr | Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures |
| title_full_unstemmed | Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures |
| title_short | Ivermectin Strengthens Paclitaxel Effectiveness in High-Grade Serous Carcinoma in 3D Cell Cultures |
| title_sort | ivermectin strengthens paclitaxel effectiveness in high grade serous carcinoma in 3d cell cultures |
| topic | 3D cultures chemoresistance drug repurposing high-grade serous carcinoma drug synergism |
| url | https://www.mdpi.com/1424-8247/18/1/14 |
| work_keys_str_mv | AT mariananunes ivermectinstrengthenspaclitaxeleffectivenessinhighgradeserouscarcinomain3dcellcultures AT sararicardo ivermectinstrengthenspaclitaxeleffectivenessinhighgradeserouscarcinomain3dcellcultures |