LAPSE:2024.1082
Published Article
LAPSE:2024.1082
Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations
June 10, 2024
Abstract
Betulinic acid is a naturally occurring pentacyclic triterpene belonging to the lupane-group that exhibits a wide range of pharmacological activities. BA derivatives are continuously being researched due to their improved anticancer efficacy and bioavailability. The current research was conducted in order to determine the antiproliferative potential of three synthesized BA fatty esters using palmitic, stearic and butyric acids and their liposomal nanoformulations. The cytotoxic potential of BA fatty esters (Pal-BA, St-BA, But-BA) and their respective liposomal formulations (Pal-BA-Lip, St-BA-Lip, But-BA-Lip) has been assessed on HaCaT immortalized human keratinocytes and A375 human melanoma cells. Both the esters and their liposomes acted as cytotoxic agents against melanoma cells in a time- and dose-dependent manner. The butyryl ester But-BA outperformed BA in terms of cytotoxicity (IC50 60.77 μM) while the nanoformulations St-BA-Lip, But-BA-Lip and BA-Lip also displayed IC50 values (60.11, 50.71 and 59.01 μM) lower compared to BA (IC50 65.9 μM). The morphological evaluation revealed that the A375 cells underwent morphological changes consistent with apoptosis following 48 h treatment with the tested compounds, while the HaCaT cells’ morphology remained unaltered. Both the esters and their liposomal formulations were able to inhibit the migration of the melanoma cells, suggesting a significant antimetastatic effect. The quantitative real-time PCR revealed that all tested samples were able to significantly increase the expression of the pro-apoptotic Bax and inhibit the anti-apoptotic Bcl-2 proteins. This effect was more potent in the case of liposomal nanoformulations versus non-encapsulated compounds, and overall, But-BA and its formulation exhibited the best results in this regard.
Betulinic acid is a naturally occurring pentacyclic triterpene belonging to the lupane-group that exhibits a wide range of pharmacological activities. BA derivatives are continuously being researched due to their improved anticancer efficacy and bioavailability. The current research was conducted in order to determine the antiproliferative potential of three synthesized BA fatty esters using palmitic, stearic and butyric acids and their liposomal nanoformulations. The cytotoxic potential of BA fatty esters (Pal-BA, St-BA, But-BA) and their respective liposomal formulations (Pal-BA-Lip, St-BA-Lip, But-BA-Lip) has been assessed on HaCaT immortalized human keratinocytes and A375 human melanoma cells. Both the esters and their liposomes acted as cytotoxic agents against melanoma cells in a time- and dose-dependent manner. The butyryl ester But-BA outperformed BA in terms of cytotoxicity (IC50 60.77 μM) while the nanoformulations St-BA-Lip, But-BA-Lip and BA-Lip also displayed IC50 values (60.11, 50.71 and 59.01 μM) lower compared to BA (IC50 65.9 μM). The morphological evaluation revealed that the A375 cells underwent morphological changes consistent with apoptosis following 48 h treatment with the tested compounds, while the HaCaT cells’ morphology remained unaltered. Both the esters and their liposomal formulations were able to inhibit the migration of the melanoma cells, suggesting a significant antimetastatic effect. The quantitative real-time PCR revealed that all tested samples were able to significantly increase the expression of the pro-apoptotic Bax and inhibit the anti-apoptotic Bcl-2 proteins. This effect was more potent in the case of liposomal nanoformulations versus non-encapsulated compounds, and overall, But-BA and its formulation exhibited the best results in this regard.
Record ID
Keywords
betulinic acid, betulinic acid derivatives, cytotoxicity, liposomal formulation, melanoma
Subject
Suggested Citation
Milan A, Mioc M, Mioc A, Marangoci N, Racoviceanu R, Mardale G, Bălan-Porcărașu M, Rotunjanu S, Şoica I, Șoica C. Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations. (2024). LAPSE:2024.1082
Author Affiliations
Milan A: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medic [ORCID]
Mioc M: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medic
Mioc A: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Marangoci N: Institute of Macromolecular Chemistry ‘Petru Poni’, 700487 Iasi, Romania [ORCID]
Racoviceanu R: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medic [ORCID]
Mardale G: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Bălan-Porcărașu M: Institute of Macromolecular Chemistry ‘Petru Poni’, 700487 Iasi, Romania [ORCID]
Rotunjanu S: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Şoica I: University College London Medical School, 74 Huntley St., London WC1E 6DE, UK
Șoica C: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Mioc M: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medic
Mioc A: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Marangoci N: Institute of Macromolecular Chemistry ‘Petru Poni’, 700487 Iasi, Romania [ORCID]
Racoviceanu R: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medic [ORCID]
Mardale G: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Bălan-Porcărașu M: Institute of Macromolecular Chemistry ‘Petru Poni’, 700487 Iasi, Romania [ORCID]
Rotunjanu S: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Şoica I: University College London Medical School, 74 Huntley St., London WC1E 6DE, UK
Șoica C: Research Centre for Pharmaco-Toxicological Evaluation, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timișoara, Romania; Department of Pharmacology-Pharmacotherapy, Faculty of Pharmacy, Victor Babes University of M
Journal Name
Processes
Volume
12
Issue
2
First Page
416
Year
2024
Publication Date
2024-02-19
ISSN
2227-9717
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PII: pr12020416, Publication Type: Journal Article
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LAPSE:2024.1082
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https://doi.org/10.3390/pr12020416
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Jun 10, 2024
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