Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells

Awatif Rashed Z. Almotairy; Diego Montagner; Liam Morrison; Michael Devereux; Orla Howe; Andrea Erxleben

doi:10.1016/j.jinorgbio.2020.111125

Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells

Awatif Rashed Z. Almotairy
, Diego Montagner
, Liam Morrison
, Michael Devereux
, Orla Howe
, Andrea Erxleben

Research output: Contribution to journal › Article › peer-review

Abstract

Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH₃)₂Cl₂(PBA)₂] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH₃)₂Cl₂(PBA)(OH)] (A), cis,cis,trans-[Pt(NH₃)₂Cl₂(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH₃)₂Cl₂(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.

Original language	English
Article number	111125
Journal	Journal of Inorganic Biochemistry
Volume	210
DOIs	https://doi.org/10.1016/j.jinorgbio.2020.111125
Publication status	Published - Sep 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Apoptosis
Cytotoxicity
DNA damage
Histone deacetylase inhibitor
Platinum(IV) complexes
Reactive oxygen species

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10.1016/j.jinorgbio.2020.111125

https://arrow.tudublin.ie/scschbioart/285Licence: CC BY-NC-SA

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Almotairy, A. R. Z., Montagner, D., Morrison, L., Devereux, M., Howe, O., & Erxleben, A. (2020). Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells. Journal of Inorganic Biochemistry, 210, Article 111125. https://doi.org/10.1016/j.jinorgbio.2020.111125

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title = "Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells",

abstract = "Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.",

keywords = "Apoptosis, Cytotoxicity, DNA damage, Histone deacetylase inhibitor, Platinum(IV) complexes, Reactive oxygen species",

author = "Almotairy, \{Awatif Rashed Z.\} and Diego Montagner and Liam Morrison and Michael Devereux and Orla Howe and Andrea Erxleben",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = sep,

doi = "10.1016/j.jinorgbio.2020.111125",

language = "English",

volume = "210",

journal = "Journal of Inorganic Biochemistry",

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publisher = "Elsevier Inc.",

}

Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells. / Almotairy, Awatif Rashed Z.; Montagner, Diego; Morrison, Liam et al.
In: Journal of Inorganic Biochemistry, Vol. 210, 111125, 09.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells

AU - Almotairy, Awatif Rashed Z.

AU - Montagner, Diego

AU - Morrison, Liam

AU - Devereux, Michael

AU - Howe, Orla

AU - Erxleben, Andrea

PY - 2020/9

Y1 - 2020/9

N2 - Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.

AB - Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.

KW - Apoptosis

KW - Cytotoxicity

KW - DNA damage

KW - Histone deacetylase inhibitor

KW - Platinum(IV) complexes

KW - Reactive oxygen species

UR - https://www.scopus.com/pages/publications/85085989280

U2 - 10.1016/j.jinorgbio.2020.111125

DO - 10.1016/j.jinorgbio.2020.111125

M3 - Article

C2 - 32521289

AN - SCOPUS:85085989280

SN - 0162-0134

VL - 210

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

M1 - 111125

ER -

Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells

Abstract

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Keywords

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