Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment
The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosyntheti...
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MDPI AG
2022-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/20/7113 |
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| author | Iqra Sarfraz Azhar Rasul Farhat Jabeen Tayyaba Sultana Şevki Adem |
| author_facet | Iqra Sarfraz Azhar Rasul Farhat Jabeen Tayyaba Sultana Şevki Adem |
| author_sort | Iqra Sarfraz |
| collection | DOAJ |
| description | The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC<sub>50</sub> values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively. For the determination of Ki constants and the inhibition type of hit compounds, Lineweaver–Burk graphs were plotted. Silibinin and ellagic acid performed the competitive inhibition of PKM2 with Ki constants of 0.61 µM and 5.06 µM, while curcumin and resveratrol were identified as non-competitive inhibitors of PKM2 with Ki constants of 1.20 µM and 7.34 µM. The in silico screening of phenolic compounds against three binding sites of PKM2 provided insight into the binding pattern and functionally important amino residues of PKM2. Further, the evaluation of cytotoxicity via MTT assay demonstrated ellagic acid as potent inhibitor of cancer cell growth (IC<sub>50</sub> = 20 µM). These results present ellagic acid, silibinin, curcumin, and resveratrol as inhibitors of PKM2 to interrogate metabolic reprogramming in cancer cells. This study has also provided the foundation for further research to validate the potential of identified bioactive entities for PKM2 targeted-cancer therapies. |
| first_indexed | 2024-03-09T19:41:47Z |
| format | Article |
| id | doaj.art-cf3642eff0d148e7949c0126b3f4e7e7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T19:41:47Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-cf3642eff0d148e7949c0126b3f4e7e72023-11-24T01:37:42ZengMDPI AGMolecules1420-30492022-10-012720711310.3390/molecules27207113Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer TreatmentIqra Sarfraz0Azhar Rasul1Farhat Jabeen2Tayyaba Sultana3Şevki Adem4Department of Zoology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad 38000, PakistanDepartment of Zoology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad 38000, PakistanDepartment of Zoology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad 38000, PakistanDepartment of Zoology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad 38000, PakistanDepartment of Chemistry, Faculty of Sciences, Cankiri Karatekin University, Cankiri 18100, TurkeyThe reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC<sub>50</sub> values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively. For the determination of Ki constants and the inhibition type of hit compounds, Lineweaver–Burk graphs were plotted. Silibinin and ellagic acid performed the competitive inhibition of PKM2 with Ki constants of 0.61 µM and 5.06 µM, while curcumin and resveratrol were identified as non-competitive inhibitors of PKM2 with Ki constants of 1.20 µM and 7.34 µM. The in silico screening of phenolic compounds against three binding sites of PKM2 provided insight into the binding pattern and functionally important amino residues of PKM2. Further, the evaluation of cytotoxicity via MTT assay demonstrated ellagic acid as potent inhibitor of cancer cell growth (IC<sub>50</sub> = 20 µM). These results present ellagic acid, silibinin, curcumin, and resveratrol as inhibitors of PKM2 to interrogate metabolic reprogramming in cancer cells. This study has also provided the foundation for further research to validate the potential of identified bioactive entities for PKM2 targeted-cancer therapies.https://www.mdpi.com/1420-3049/27/20/7113tumor metabolismpyruvate kinase M2phytochemicalsenzymatic assay |
| spellingShingle | Iqra Sarfraz Azhar Rasul Farhat Jabeen Tayyaba Sultana Şevki Adem Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment Molecules tumor metabolism pyruvate kinase M2 phytochemicals enzymatic assay |
| title | Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment |
| title_full | Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment |
| title_fullStr | Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment |
| title_full_unstemmed | Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment |
| title_short | Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment |
| title_sort | identification of natural compounds as inhibitors of pyruvate kinase m2 for cancer treatment |
| topic | tumor metabolism pyruvate kinase M2 phytochemicals enzymatic assay |
| url | https://www.mdpi.com/1420-3049/27/20/7113 |
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