LC-mHTT-AN2 oversees lactate transport, hypoxia, and glucose homeostasis through dual regulation of MCT-1/4 in the tumor microenvironment
Abstract Background Cancer cells have accelerated glycolysis rate, resulting in excessive lactate generation, which is critical in rapidly growing cancerous cells. Lactate is primarily transported by MCT-1/MCT-4, the two H+/lactate transporters that promote cellular proliferation and growth. Through in-silico, in-vitro, and in-vivo investigation, we aimed to find new dual MCT-1 and MCT-4 inhibitor for therapeutic intervention in breast cancer. Material and Methods A library of 4098 natural product-like compounds (HY-L057L) was retrieved and screened based on structural similarity with Syrosingopine (above70%). Among them, we found LC-mHTT-AN2 as a potential molecule that inhibits MCT-1 and MCT-4 symporters through docking study, pharmacokinetic(ADMET) profiling.Further, compound was tested for the in-vitro cytotoxicity(via MTTassay) and antiapototic activity ( via DAPI, AO/EtBr,JC-1) against MCF-7 cells. we also examined the in-vivo anticancer activity against MNU (Methyl Nitrosourea) induced mammary gland carcinoma in Wistar rat through carmine staining, SEM,biochemical and western blotting analysis Results Our in-silico result revealed that LC-mHTT-AN2 has good docking score with both proteins( MCT-1 and MCT-4 ) and favourable ADMET profiling. Further ,in-vitro result demonstrated that LC-mHTT-AN2 has significant IC50 value (4.7µM) and antiapoptotic potential. Once scrutinized against MNU-induced mammary gland carcinoma, LC-mHTT-AN2 significantly restored the altered morphology and ameliorated histopathological, biochemical and lactate production. Furthermore, the western blotting analysis revealed that LC-mHTT-AN2 significantly regulate mitochondrial apoptotic pathway and has demarcating effect upon inhibition of lactate transport and hypoxic microenvironment, demonstrating the preclinical efficacy for treating breast cancer. Conclusions The overall findings from in -silico, in -vitro, and in -vivo support the pre-clinical efficacy of LC-mHTT-AN2 in the treatment of breast carcinoma by combined inhibition of MCT-1 and MCT-4. Further research is needed to verify its usefulness before clinical application..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ResearchSquare.com - (2024) vom: 11. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yadav, Sneha [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-3981481/v1 |
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XRA042651883 |
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| 520 | |a Abstract Background Cancer cells have accelerated glycolysis rate, resulting in excessive lactate generation, which is critical in rapidly growing cancerous cells. Lactate is primarily transported by MCT-1/MCT-4, the two H+/lactate transporters that promote cellular proliferation and growth. Through in-silico, in-vitro, and in-vivo investigation, we aimed to find new dual MCT-1 and MCT-4 inhibitor for therapeutic intervention in breast cancer. Material and Methods A library of 4098 natural product-like compounds (HY-L057L) was retrieved and screened based on structural similarity with Syrosingopine (above70%). Among them, we found LC-mHTT-AN2 as a potential molecule that inhibits MCT-1 and MCT-4 symporters through docking study, pharmacokinetic(ADMET) profiling.Further, compound was tested for the in-vitro cytotoxicity(via MTTassay) and antiapototic activity ( via DAPI, AO/EtBr,JC-1) against MCF-7 cells. we also examined the in-vivo anticancer activity against MNU (Methyl Nitrosourea) induced mammary gland carcinoma in Wistar rat through carmine staining, SEM,biochemical and western blotting analysis Results Our in-silico result revealed that LC-mHTT-AN2 has good docking score with both proteins( MCT-1 and MCT-4 ) and favourable ADMET profiling. Further ,in-vitro result demonstrated that LC-mHTT-AN2 has significant IC50 value (4.7µM) and antiapoptotic potential. Once scrutinized against MNU-induced mammary gland carcinoma, LC-mHTT-AN2 significantly restored the altered morphology and ameliorated histopathological, biochemical and lactate production. Furthermore, the western blotting analysis revealed that LC-mHTT-AN2 significantly regulate mitochondrial apoptotic pathway and has demarcating effect upon inhibition of lactate transport and hypoxic microenvironment, demonstrating the preclinical efficacy for treating breast cancer. Conclusions The overall findings from in -silico, in -vitro, and in -vivo support the pre-clinical efficacy of LC-mHTT-AN2 in the treatment of breast carcinoma by combined inhibition of MCT-1 and MCT-4. Further research is needed to verify its usefulness before clinical application. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Singh, Jyoti |4 aut | |
| 700 | 1 | |a Kumar, Rohit |4 aut | |
| 700 | 1 | |a Sonkar, Archana Bharti |4 aut | |
| 700 | 1 | |a Kumar, Anurag |4 aut | |
| 700 | 1 | |a Kumar, Dharmendra |4 aut | |
| 700 | 1 | |a Alamoudi, Mariam K. |4 aut | |
| 700 | 1 | |a Ansari, Mohd Nazam |4 aut | |
| 700 | 1 | |a Saeedan, Abdulaziz S. |4 aut | |
| 700 | 1 | |a Mukherjee, Alok |4 aut | |
| 700 | 1 | |a Kaithwas, Gaurav |4 aut | |
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