Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer
Acquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of the oncogenic PI3K/Akt signaling axis and overexpression of cisplatin-exporter MRP2 along with prosurvival effectors NF-κB and IAPs i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.803114/full |
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| author | Elizabeth Mahapatra Debomita Sengupta Ravindra Kumar Budheswar Dehury Salini Das Madhumita Roy Sutapa Mukherjee |
| author_facet | Elizabeth Mahapatra Debomita Sengupta Ravindra Kumar Budheswar Dehury Salini Das Madhumita Roy Sutapa Mukherjee |
| author_sort | Elizabeth Mahapatra |
| collection | DOAJ |
| description | Acquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of the oncogenic PI3K/Akt signaling axis and overexpression of cisplatin-exporter MRP2 along with prosurvival effectors NF-κB and IAPs in cervical cancer cells. These activated prosurvival signaling cascades drive drug efflux and evasion of apoptosis for rendering drug-resistant phenotypes. Our study challenges the PI3K/Akt axis in a cisplatin-resistant cervical cancer scenario with phenethylisothiocyanate (PEITC) for chemosensitization of SiHaR, a cisplatin-resistant sub-line of SiHa and 3-methylcholanthrene–induced cervical cancer mice models. SiHaR exhibited higher MRP2, p-AktThr308, NF-κB, XIAP, and survivin expressions which cumulatively compromised cisplatin retention capacity and accumulated PEITC better than SiHa. SiHaR appeared to favor PEITC uptake as its accumulation rates were found to be positively correlated with MRP2 expressions. PEITC treatment in SiHaR for 3 h prior to cisplatin exposure revived intracellular platinum levels, reduced free GSH levels, generated greater ROS, and altered mitochondrial membrane potential compared to SiHa. Western blot and immunofluorescence results indicated that PEITC successfully downregulated MRP2 in addition to suppressing p-AktThr308, XIAP, survivin, and NF-κB expressions. In mice models, administration of 5 mg/kg body-weight PEITC priming dosage prior to treatment with 3 mg/kg body-weight of cisplatin remediated cervical histology and induced tumor regression in contrast to the group receiving the same dosage of cisplatin only. This suggested PEITC as a potential chemosensitizing agent in light of acquired cisplatin resistance in cervical cancer and established its candidature for Phase I clinical trial. |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T23:11:22Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-5b4e411784a1485ba29a8151383c80b62022-12-22T00:08:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-04-011310.3389/fphar.2022.803114803114Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical CancerElizabeth Mahapatra0Debomita Sengupta1Ravindra Kumar2Budheswar Dehury3Salini Das4Madhumita Roy5Sutapa Mukherjee6Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, IndiaDepartment of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, IndiaSchool of Biotechnology, National Institute of Technology Calicut, Kozhikode, IndiaICMR-Regional Medical Research Centre, Chandrasekharpur, Bhubaneswar, IndiaDepartment of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, IndiaDepartment of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, IndiaDepartment of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, IndiaAcquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of the oncogenic PI3K/Akt signaling axis and overexpression of cisplatin-exporter MRP2 along with prosurvival effectors NF-κB and IAPs in cervical cancer cells. These activated prosurvival signaling cascades drive drug efflux and evasion of apoptosis for rendering drug-resistant phenotypes. Our study challenges the PI3K/Akt axis in a cisplatin-resistant cervical cancer scenario with phenethylisothiocyanate (PEITC) for chemosensitization of SiHaR, a cisplatin-resistant sub-line of SiHa and 3-methylcholanthrene–induced cervical cancer mice models. SiHaR exhibited higher MRP2, p-AktThr308, NF-κB, XIAP, and survivin expressions which cumulatively compromised cisplatin retention capacity and accumulated PEITC better than SiHa. SiHaR appeared to favor PEITC uptake as its accumulation rates were found to be positively correlated with MRP2 expressions. PEITC treatment in SiHaR for 3 h prior to cisplatin exposure revived intracellular platinum levels, reduced free GSH levels, generated greater ROS, and altered mitochondrial membrane potential compared to SiHa. Western blot and immunofluorescence results indicated that PEITC successfully downregulated MRP2 in addition to suppressing p-AktThr308, XIAP, survivin, and NF-κB expressions. In mice models, administration of 5 mg/kg body-weight PEITC priming dosage prior to treatment with 3 mg/kg body-weight of cisplatin remediated cervical histology and induced tumor regression in contrast to the group receiving the same dosage of cisplatin only. This suggested PEITC as a potential chemosensitizing agent in light of acquired cisplatin resistance in cervical cancer and established its candidature for Phase I clinical trial.https://www.frontiersin.org/articles/10.3389/fphar.2022.803114/fullPEITCchemosensitizationcisplatin resistanceMRP2PI3K/AKT |
| spellingShingle | Elizabeth Mahapatra Debomita Sengupta Ravindra Kumar Budheswar Dehury Salini Das Madhumita Roy Sutapa Mukherjee Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer Frontiers in Pharmacology PEITC chemosensitization cisplatin resistance MRP2 PI3K/AKT |
| title | Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer |
| title_full | Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer |
| title_fullStr | Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer |
| title_full_unstemmed | Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer |
| title_short | Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer |
| title_sort | phenethylisothiocyanate potentiates platinum therapy by reversing cisplatin resistance in cervical cancer |
| topic | PEITC chemosensitization cisplatin resistance MRP2 PI3K/AKT |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.803114/full |
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