Phani Krishna Parcha1,2, Sailu Sarvagalla3, Cheemala Ashok4, S J Sudharshan1,2, Madhu Dyavaiah1,2, Mohane Selvaraj Coumar5, Baskaran Rajasekaran1,2. 1. Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, India. 2. DBT-Interdisciplinary Program in Life Sciences, School of Life Sciences, Pondicherry University, Puducherry, India. 3. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India. 4. Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India. 5. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India. mohane@bicpu.edu.in.
Abstract
BACKGROUND: Papaverine is a benzylisoquinoline alkaloid from the plant Papaver somniferum (Opium poppy). It is approved as an antispasmodic drug by the US FDA and is also reported to have anti-cancer properties. Here, Papaverine's activity in chronic myeloid leukemia (CML) is explored using Saccharomyces cerevisiae, mammalian cancer cell lines, and in silico studies. METHODS: The sensitivity of wild-type and mutant (anti-oxidant defense, apoptosis) strains of S. cerevisiae to the drug Papaverine was tested by colony formation, spot assays, and AO/EB staining. In vitro cytotoxic effect was investigated on HCT15 (colon), A549 (lung), HeLa (cervical), and K562 (Bcr-Abl positive CML), and RAW 264.7 cell lines; cell cycle, mitochondrial membrane potential, ROS detection analyzed in K562 cells using flow cytometry and apoptotic markers, Bcr-Abl signaling pathways examined by western blotting. Molecular docking and molecular dynamics simulation of Papaverine against the target Bcr-Abl were also carried out. RESULTS: Investigation in S. cerevisiae evidenced Papaverine induces ROS-mediated apoptosis. Subsequent in vitro examination showed that CML cell line K562 was more sensitive to the drug Papaverine. Papaverine induces ROS generation, promotes apoptosis, and inhibits Bcr-Abl downstream signaling. Papaverine acts synergistically with the drug Imatinib. Furthermore, the docking and molecular dynamic simulation studies supported that Papaverine binds to the allosteric site of Bcr-Abl. CONCLUSION: The data presented here have added support to the concept of polypharmacology of existing drugs and natural compounds to interact with more than one target. This study provides a proof-of-concept for repositioning Papaverine as an anti-CML drug.
BACKGROUND:Papaverine is a benzylisoquinoline alkaloid from the plant Papaver somniferum (Opium poppy). It is approved as an antispasmodic drug by the US FDA and is also reported to have anti-cancer properties. Here, Papaverine's activity in chronic myeloid leukemia (CML) is explored using Saccharomyces cerevisiae, mammaliancancer cell lines, and in silico studies. METHODS: The sensitivity of wild-type and mutant (anti-oxidant defense, apoptosis) strains of S. cerevisiae to the drug Papaverine was tested by colony formation, spot assays, and AO/EB staining. In vitro cytotoxic effect was investigated on HCT15 (colon), A549 (lung), HeLa (cervical), and K562 (Bcr-Abl positive CML), and RAW 264.7 cell lines; cell cycle, mitochondrial membrane potential, ROS detection analyzed in K562 cells using flow cytometry and apoptotic markers, Bcr-Abl signaling pathways examined by western blotting. Molecular docking and molecular dynamics simulation of Papaverine against the target Bcr-Abl were also carried out. RESULTS: Investigation in S. cerevisiae evidenced Papaverine induces ROS-mediated apoptosis. Subsequent in vitro examination showed that CML cell line K562 was more sensitive to the drug Papaverine. Papaverine induces ROS generation, promotes apoptosis, and inhibits Bcr-Abl downstream signaling. Papaverine acts synergistically with the drug Imatinib. Furthermore, the docking and molecular dynamic simulation studies supported that Papaverine binds to the allosteric site of Bcr-Abl. CONCLUSION: The data presented here have added support to the concept of polypharmacology of existing drugs and natural compounds to interact with more than one target. This study provides a proof-of-concept for repositioning Papaverine as an anti-CML drug.
Authors: Thomas O'Hare; Michael W N Deininger; Christopher A Eide; Tim Clackson; Brian J Druker Journal: Clin Cancer Res Date: 2010-11-22 Impact factor: 12.531
Authors: Abdur Rauf; Muhammad Akram; Prabhakar Semwal; Adil A H Mujawah; Naveed Muhammad; Zerfishan Riaz; Naveed Munir; Dmitry Piotrovsky; Irina Vdovina; Abdelhakim Bouyahya; Charles Oluwaseun Adetunji; Mohammad Ali Shariati; Zainab M Almarhoon; Yahia N Mabkhot; Haroon Khan Journal: Oxid Med Cell Longev Date: 2021-11-11 Impact factor: 6.543