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Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies

Murraya koenigii is well documented in the Indian ancient medical text “Charaka Samhita.” The carbazole alkaloid “mahanine” from this plant exhibited anticancer activity against several cancers. Here, we have taken a comprehensive study to standardize the method for the preparation of a mahanine-enr...

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Autores principales: Satyavarapu, Eswara Murali, Sinha, Prasun Kumar, Mandal, Chitra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439207/
https://www.ncbi.nlm.nih.gov/pubmed/32851075
http://dx.doi.org/10.1155/2020/4638132
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author Satyavarapu, Eswara Murali
Sinha, Prasun Kumar
Mandal, Chitra
author_facet Satyavarapu, Eswara Murali
Sinha, Prasun Kumar
Mandal, Chitra
author_sort Satyavarapu, Eswara Murali
collection PubMed
description Murraya koenigii is well documented in the Indian ancient medical text “Charaka Samhita.” The carbazole alkaloid “mahanine” from this plant exhibited anticancer activity against several cancers. Here, we have taken a comprehensive study to standardize the method for the preparation of a mahanine-enriched fraction (MEF) with the highest yield and defined markers. Our optimized method produced MEF having the highest amount of mahanine, a major marker, with excellent in vitro antiproliferative activity against ovarian and breast cancer cells as evidenced by decreased cell viability by MTT assay. Moreover, it exhibited condensed and fragmented nuclei by DAPI staining and increased annexin V-/PI-stained cells after MEF treatment, indicating apoptosis. It also exhibited good efficacy in ovarian and breast cancer syngeneic mice models, with an ED50 of 300 mg/kg body weight (BW). MEF is stable up to 40°C for ≥3 months. Its biological activity remains unchanged at a wide range of pH (1-10) for up to ~3 hours, indicating a safe oral route of administration. Additionally, the comparative pharmacokinetics of MEF and mahanine in rats showed a 31% higher bioavailability of mahanine in MEF-fed rats compared to rats fed with mahanine alone. Furthermore, mice fed with MEF at 5000 mg/kg BW single dose, 300-1500 mg/kg BW/day for 14 days, and 300 mg/kg BW/day for 28, 90, and 180 days for subacute, subchronic, chronic studies, respectively, did not show any significant clinical signs of toxicity, behavioral changes, mortality, organ weights, serum biochemistry, and hematological parameters indicating no/minimum toxicity for up to 180 days. To the best of our knowledge, this is the first report showing the pH/temperature stability and chronic toxicity studies of MEF along with in vivo efficacy against breast cancer. Taken together, our study will enhance the commercial value of this highly potential medicinal plant and will be helpful as a reference material for its clinical development.
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spelling pubmed-74392072020-08-25 Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies Satyavarapu, Eswara Murali Sinha, Prasun Kumar Mandal, Chitra Biomed Res Int Research Article Murraya koenigii is well documented in the Indian ancient medical text “Charaka Samhita.” The carbazole alkaloid “mahanine” from this plant exhibited anticancer activity against several cancers. Here, we have taken a comprehensive study to standardize the method for the preparation of a mahanine-enriched fraction (MEF) with the highest yield and defined markers. Our optimized method produced MEF having the highest amount of mahanine, a major marker, with excellent in vitro antiproliferative activity against ovarian and breast cancer cells as evidenced by decreased cell viability by MTT assay. Moreover, it exhibited condensed and fragmented nuclei by DAPI staining and increased annexin V-/PI-stained cells after MEF treatment, indicating apoptosis. It also exhibited good efficacy in ovarian and breast cancer syngeneic mice models, with an ED50 of 300 mg/kg body weight (BW). MEF is stable up to 40°C for ≥3 months. Its biological activity remains unchanged at a wide range of pH (1-10) for up to ~3 hours, indicating a safe oral route of administration. Additionally, the comparative pharmacokinetics of MEF and mahanine in rats showed a 31% higher bioavailability of mahanine in MEF-fed rats compared to rats fed with mahanine alone. Furthermore, mice fed with MEF at 5000 mg/kg BW single dose, 300-1500 mg/kg BW/day for 14 days, and 300 mg/kg BW/day for 28, 90, and 180 days for subacute, subchronic, chronic studies, respectively, did not show any significant clinical signs of toxicity, behavioral changes, mortality, organ weights, serum biochemistry, and hematological parameters indicating no/minimum toxicity for up to 180 days. To the best of our knowledge, this is the first report showing the pH/temperature stability and chronic toxicity studies of MEF along with in vivo efficacy against breast cancer. Taken together, our study will enhance the commercial value of this highly potential medicinal plant and will be helpful as a reference material for its clinical development. Hindawi 2020-08-10 /pmc/articles/PMC7439207/ /pubmed/32851075 http://dx.doi.org/10.1155/2020/4638132 Text en Copyright © 2020 Eswara Murali Satyavarapu et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Satyavarapu, Eswara Murali
Sinha, Prasun Kumar
Mandal, Chitra
Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title_full Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title_fullStr Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title_full_unstemmed Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title_short Preclinical Development of Mahanine-Enriched Fraction from Indian Spice Murraya koenigii for the Management of Cancer: Efficacy, Temperature/pH stability, Pharmacokinetics, Acute and Chronic Toxicity (14-180 Days) Studies
title_sort preclinical development of mahanine-enriched fraction from indian spice murraya koenigii for the management of cancer: efficacy, temperature/ph stability, pharmacokinetics, acute and chronic toxicity (14-180 days) studies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439207/
https://www.ncbi.nlm.nih.gov/pubmed/32851075
http://dx.doi.org/10.1155/2020/4638132
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