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Targeted inhibition of colorectal cancer proliferation: The dual-modulatory role of 2,4-DTBP on anti-apoptotic Bcl-2 and Survivin proteins.
Saha, Partha; Hegde, Mangala; Chakraborty, Kanak; Singha, Achinta; Mukerjee, Nobendu; Ghosh, Deepshikha; Kunnumakkara, Ajaikumar B; Khan, Mohd Shahnawaz; Ahmad, Md Irshad; Ghosh, Arabinda; Kumer, Ajoy; Sil, Samir Kumar.
Afiliación
  • Saha P; Molecular Genetics and Cell Physiology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, India.
  • Hegde M; Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India.
  • Chakraborty K; Molecular Genetics and Cell Physiology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, India.
  • Singha A; Molecular Genetics and Cell Physiology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, India.
  • Mukerjee N; Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.
  • Ghosh D; Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, New South Wales, Australia.
  • Kunnumakkara AB; Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
  • Khan MS; Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, India.
  • Ahmad MI; Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
  • Ghosh A; Department of Structural Biology, School of Medicine, UTHEALTH Science Center, San Antonio, Texas, USA.
  • Kumer A; Department of Computational Biology and Biotechnology, Mahapurusha Srimanta Sankaradeva Viswavidalaya, Guwahati, Assam, India.
  • Sil SK; Department of Chemistry, College of Arts and Sciences, IUBAT-International University of Business Agriculture and Technology, Dhaka, Bangladesh.
J Cell Mol Med ; 28(7): e18150, 2024 04.
Article en En | MEDLINE | ID: mdl-38494866
ABSTRACT
The anti-apoptotic proteins, Bcl-2 and Survivin, are consistently overexpressed in numerous human malignancies, notably in colorectal cancer. 2,4-Di-tert-butylphenol (2,4-DTBP) is a naturally occurring phenolic compound known for its diverse biological activities, including anti-cancer properties. The mechanism behind 2,4-DTBP-induced inhibition of cell proliferation and apoptosis in human colorectal cancer cells, specifically regarding Bcl-2 and Survivin, remains to be elucidated. In this study, we employed both in silico and in vitro methodologies to underpin this interaction at the molecular level. Molecular docking demonstrated a substantial binding affinity of 2,4-DTBP towards Bcl-2 (ΔG = -9.8 kcal/mol) and Survivin (ΔG = -5.6 kcal/mol), suggesting a potential inhibitory effect. Further, molecular dynamic simulations complemented by MM-GBSA calculations confirmed the significant binding of 2,4-DTBP with Bcl-2 (dGbind = -54.85 ± 6.79 kcal/mol) and Survivin (dGbind = -32.36 ± 1.29 kcal/mol). In vitro assays using HCT116 colorectal cancer cells revealed that 2,4-DTBP inhibited proliferation and promoted apoptosis in both a dose- and time-dependent manner. Fluorescence imaging and scanning electron microscopy illustrated the classical features associated with apoptosis upon 2,4-DTBP exposure. Cell cycle analysis through flow cytometry highlighted a G1 phase arrest and apoptosis assay demonstrated increased apoptotic cell population. Notably, western blotting results indicated a decreased expression of Bcl-2 and Survivin post-treatment. Considering the cytoprotective roles of Bcl-2 and Survivin through the inhibition of mitochondrial dysfunction, our findings of disrupted mitochondrial bioenergetics, characterized by reduced ATP production and oxygen consumption, further accentuate the functional impairment of these proteins. Overall, the integration of in silico and in vitro data suggests that 2,4-DTBP holds promise as a therapeutic agent targeting Bcl-2 and Survivin in colorectal cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenoles / Neoplasias Colorrectales Límite: Humans Idioma: En Revista: J Cell Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenoles / Neoplasias Colorrectales Límite: Humans Idioma: En Revista: J Cell Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido