Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma
Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inab...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.625899/full |
| _version_ | 1818700668462956544 |
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| author | Malobika Chakravarty Piyali Ganguli Piyali Ganguli Manikanta Murahari Ram Rup Sarkar Ram Rup Sarkar Godefridus Johannes Peters Godefridus Johannes Peters Y. C. Mayur |
| author_facet | Malobika Chakravarty Piyali Ganguli Piyali Ganguli Manikanta Murahari Ram Rup Sarkar Ram Rup Sarkar Godefridus Johannes Peters Godefridus Johannes Peters Y. C. Mayur |
| author_sort | Malobika Chakravarty |
| collection | DOAJ |
| description | Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma. |
| first_indexed | 2024-12-17T15:08:36Z |
| format | Article |
| id | doaj.art-ba35824f48544d86a1679afe531fba6d |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-17T15:08:36Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ba35824f48544d86a1679afe531fba6d2022-12-21T21:43:44ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.625899625899Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant GliomaMalobika Chakravarty0Piyali Ganguli1Piyali Ganguli2Manikanta Murahari3Ram Rup Sarkar4Ram Rup Sarkar5Godefridus Johannes Peters6Godefridus Johannes Peters7Y. C. Mayur8Department of Pharmaceutical Chemistry, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, IndiaChemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, IndiaChemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaDepartment of Biochemistry, Medical University of Gdansk, Gdansk, PolandLaboratory Medical Oncology, Amsterdam University Medical Centers, Location VUMC, Amsterdam, NetherlandsDepartment of Pharmaceutical Chemistry, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, IndiaDrug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.https://www.frontiersin.org/articles/10.3389/fonc.2021.625899/fullacridone derivativesdrug combinationssynergy indexmathematical modelGliomadrug resistance |
| spellingShingle | Malobika Chakravarty Piyali Ganguli Piyali Ganguli Manikanta Murahari Ram Rup Sarkar Ram Rup Sarkar Godefridus Johannes Peters Godefridus Johannes Peters Y. C. Mayur Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma Frontiers in Oncology acridone derivatives drug combinations synergy index mathematical model Glioma drug resistance |
| title | Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma |
| title_full | Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma |
| title_fullStr | Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma |
| title_full_unstemmed | Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma |
| title_short | Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma |
| title_sort | study of combinatorial drug synergy of novel acridone derivatives with temozolomide using in silico and in vitro methods in the treatment of drug resistant glioma |
| topic | acridone derivatives drug combinations synergy index mathematical model Glioma drug resistance |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.625899/full |
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