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Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism

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dc.contributor.authorRawat, Shiv Govind
dc.contributor.authorTiwari, Rajan Kumar
dc.contributor.authorJaiswara, Pradip Kumar
dc.contributor.authorGupta, Vishal Kumar
dc.contributor.authorSonker, Pratishtha
dc.contributor.authorVishvakarma, Naveen Kumar
dc.contributor.authorKumar, Santosh
dc.contributor.authorPathak, Chandramani
dc.contributor.authorGautam, Vibhav
dc.contributor.authorKumar, Ajay
dc.date.accessioned2025-01-27T09:53:44Z
dc.date.available2025-01-27T09:53:44Z
dc.date.issued2022
dc.description.abstractCyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1?) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
dc.identifier.doihttps://doi.org/10.1007/s10495-022-01741-0
dc.identifier.issn13608185
dc.identifier.urihttps://dl.bhu.ac.in/ir/handle/123456789/13364
dc.publisherSpringer
dc.subjectAltered glucose metabolism
dc.subjectApoptosis
dc.subjectChemosensitization
dc.subjectSildenafil
dc.subjectT cell lymphoma
dc.titlePhosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism
dc.typeArticle
dspace.entity.typePublication
journal.titleApoptosis
journalvolume.identifier.volume27

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2022