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Review
. 2024 Jun 18;10(12):e33052.
doi: 10.1016/j.heliyon.2024.e33052. eCollection 2024 Jun 30.

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat

Nasreddine El Omari  1 , Asaad Khalid  2   3 , Hafiz A Makeen  4 , Hassan A Alhazmi  2   5 , Mohammed Albratty  5 , Syam Mohan  2   6 , Ching Siang Tan  7 , Long Chiau Ming  8 , Jack Bee Chook  8 , Abdelhakim Bouyahya  9
Affiliations
Review

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat

Nasreddine El Omari et al. Heliyon. .

Abstract

The Food and Drug Administration (FDA) has approved vorinostat, also called Zolinza®, for its effectiveness in fighting cancer. This drug is a suberoyl-anilide hydroxamic acid belonging to the class of histone deacetylase inhibitors (HDACis). Its HDAC inhibitory potential allows it to accumulate acetylated histones. This, in turn, can restore normal gene expression in cancer cells and activate multiple signaling pathways. Experiments have proven that vorinostat induces histone acetylation and cytotoxicity in many cancer cell lines, increases the level of p21 cell cycle proteins, and enhances pro-apoptotic factors while decreasing anti-apoptotic factors. Additionally, it regulates the immune response by up-regulating programmed death-ligand 1 (PD-L1) and interferon gamma receptor 1 (IFN-γR1) expression, and can impact proteasome and/or aggresome degradation, endoplasmic reticulum function, cell cycle arrest, apoptosis, tumor microenvironment remodeling, and angiogenesis inhibition. In this study, we sought to elucidate the precise molecular mechanism by which Vorinostat inhibits HDACs. A deeper understanding of these mechanisms could improve our understanding of cancer cell abnormalities and provide new therapeutic possibilities for cancer treatment.

Keywords: Apoptosis; Cancer; Cell death; Clinical efficacy; Epigenetic pathways; Human and disease; Medicine; Oncology.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Chemical structure of vorinostat.
Fig. 2
Fig. 2
Molecular targets are activated and/or inhibited indirectly through HDAC inhibition by vorinostat. The inhibition of HDAC by Vorinostat induces several changes in different mechanisms related to anticancer effects. These mechanisms include: 1) an increase of apoptosis, cell sensitivity, and chemotherapy sensitivity, 2) a decrease of cell proliferation and survival, 3) a decrease of metastasis and EMT, 4) a decrease of chemoresistance.Abbreviations: JNK: Jun N-terminal kinase; BMP: Bone morphogenetic protein; PI3k: phosphatidylinositol-3 kinase; mTOR: mammalian/mechanistic target of rapamycin; EMT: Epithelial–mesenchymal transition; HDAC: Histone deacetylase; HAT: Histone Acetyltransferases; STAT: signal transducer and activator of transcription; Mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; Akt: protein kinase B.
Fig. 3
Fig. 3
Anticancer actions of vorinostat combined with epigallocatechin-3-gallate. Vorinostat combined with EGCG can decrease MMP, migration and invasion, and PARP expression, and inhibits tumor cell growth. Both molecules induce indirectly an increase ROS production and Bax/Bcl2 ratio in mitochondria which induce the expression of caspase-7, and caspase-3 and therefore and apoptotic action of cancer cell.Abbreviations: MMP: matrix metalloproteinase; ROS: reactive oxygen species; PARP: poly-ADP ribose polymerase; Bcl-2: B-cell lymphoma protein 2; Bax: Bcl-2-associated X.
Fig. 4
Fig. 4
Phenotype consequences of HDAC inhibiting by vorinostat in cancer cells. The inhibitory effect of HDAC by vorinostat can induce the activation and/or the inhibition of different transcriptional factors like NF-κB, Akt, P53, STAT3, HIF-α, and Hsp90. Gene activation depending on these transcriptional factors can lead to protective phenotypes against cancer cells.Abbreviations: STAT3: signal transducer and activator of transcription 3; NF-κB: Mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; Akt: protein kinase B.
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