TY - JOUR
T1 - Mahanimbine isolated from Murraya koenigii inhibits P-glycoprotein involved in lung cancer chemoresistance
AU - Mondal, Priya
AU - Natesh, Jagadish
AU - Abdul Salam, Abdul Ajees
AU - Meeran, Syed Musthapa
N1 - Funding Information:
Dr. Abdul Ajees Abdul Salam acknowledges the research grant provided by the Manipal Academy of Higher Education (MAHE) under intramural funding (MAHE/DREG/Ph.D./IMF/2019). PM and JN acknowledge CSIR-UGC and DBT, Govt. of India, for the research fellowships. The authors are also grateful to the Director, CSIR-CFTRI, for providing support and infrastructure facilities.
Funding Information:
Dr. Abdul Ajees Abdul Salam acknowledges the research grant provided by the Manipal Academy of Higher Education (MAHE) under intramural funding (MAHE/DREG/Ph.D./IMF/2019). PM and JN acknowledge CSIR-UGC and DBT, Govt. of India, for the research fellowships. The authors are also grateful to the Director, CSIR-CFTRI, for providing support and infrastructure facilities.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/12
Y1 - 2022/12
N2 - P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.
AB - P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.
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U2 - 10.1016/j.bioorg.2022.106170
DO - 10.1016/j.bioorg.2022.106170
M3 - Article
AN - SCOPUS:85138835593
SN - 0045-2068
VL - 129
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 106170
ER -
