Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Almotairy, Awatif Rashed Z.; Gandin, Valentina; Morrison, Liam; Marzano, Cristina; Montagner, Diego; Erxleben, Andrea

doi:10.1016/j.jinorgbio.2017.09.009

Cited by 40 publications

(26 citation statements)

References 59 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that the toxic effect of some Pt IV derivatives of cisplatin, oxaliplatin, or carboplatin in cancer cells is accompanied by the mitochondrial membrane potential disruption, which affects mitochondrial functions . In cells undergoing apoptosis, the loss of mitochondrial membrane potential is often accompanied by the release of cytochrome c from mitochondria into the cytosol and represents an early step in the mitochondria‐dependent apoptotic process.…”

Section: Resultsmentioning

confidence: 99%

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Kostrhunová

Petruzzella

Gibson

et al. 2019

Chemistry A European J

View full text Add to dashboard Cite

Dual‐ or multi‐action PtIV prodrugs represent a new generation of platinum anticancer drugs. The important property of these PtIV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple‐action” prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the PtIV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9 nm (HCT‐116) to 74 nm (MDA‐MB‐231)]. It is also demonstrated that cellular activation of the PtIV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the PtIV prodrug introduced in this study acts as a true “multi‐action” prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells.

show abstract

Section: Resultsmentioning

confidence: 99%

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Kostrhunová

Petruzzella

Gibson

et al. 2019

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…Octanol–water partition coefficient (log P o/w ) of the organotin(IV) derivatives were determined by the shake flask method . All experiments were carried out in duplicate.…”

Section: Methodsmentioning

confidence: 99%

Structure‐cytotoxicity relationship for apoptotic inducers organotin(IV) derivatives of mandelic acid and L‐proline and their mixed ligand complexes having enhanced cytotoxicity

Nath

Roy

Mishra

et al. 2018

Applied Organom Chemis

View full text Add to dashboard Cite

Structure‐cytotoxicity relationship of di−/tri‐organotin(IV) derivatives of mandelic acid (1–4), L‐proline (5–7, 15, 16), and mixed ligand complexes of latter with 1,10‐phenanthroline (8–14) investigated on the basis of MTT assay against human cancer cell lines, viz. MCF‐7 (mammary cancer), HepG2 (liver cancer) and PC‐3 (prostate cancer) in vitro indicated that all complexes except methyl‐ and octyl‐ analogues displayed potential cytotoxicity. The most active one is dibutyltin(IV) mandelate (2) exhibiting IC50 2.03 ± 0.40, 0.98 ± 0.23 and 3.86 ± 1.68 μM against MCF‐7, HepG2 and PC‐3, respectively, which is ≈ 15 and 2.5 times against MCF‐7, 20 and 5 times against HepG2 and 5 and ≈ 3 times against PC‐3 more cytotoxic than cis‐platin and 5‐fluorouracil, respectively. Diorganotin(IV) derivatives of mandelic acid are more cytotoxic than triorganotin analogues. Organotin(IV) derivatives of L‐proline (except Bu3Sn(Pro) 16) are less cytotoxic than those of mandelic acid but their cytotoxicity is enhanced by complexion with 1,10‐phenanthroline. This may be due to the structural planarity and extended π system of 1,10‐phenanthroline which facilitates their transportation across the cell membrane and enhances the possibility of DNA intercalation over the planar L‐proline ring, and eventually, their DNA binding affinity so as to interfere with the cellular functions of DNA leading to apoptosis. Various biophysical experiments such as DNA fragmentation, acridine orange and comet assays, and flow cytometry assay using annexin V–fluorescein isothiocyanate (FITC) and propidium iodide (PI) have been carried out in order to ascertain their mode of action. The observed results indicated that the major cause of cancer cell death is apoptosis, but a minor role played by necrosis cannot be excluded. It is concluded on the basis of the observed results that the nature and number of organic groups bonded to tin as well as the nature of counter anions play an important role in determining the cytotoxicity of organotin(IV) compounds.

show abstract

“…It was documented that it can be used as a sensitizing agent to overcome the resistance in NSCLC cells when combined with cisplatin, gefitinib or erlotinib (36). Another study demonstrated the synergistic pro-apoptotic activity of phenylbutyric acid (PBA) and platinum(IV) derivatives in pancreatic, cervical and colon cancer cells (37).…”

Section: Butyric Propionic and Phenylbutyric Acidmentioning

confidence: 99%

“…Some SCFAs, including butyric and propionic acid, are produced by friendly bacteria in the human gut. This production mainly occurs in large intestine through multiple interactions between the gut microbiota and dietary compounds (37,40). Recently, these SCFAs became the most thoroughly studied compounds among gut microbiota metabolites.…”

Section: Short-chain Fatty Acids and Human Gut Microbiotamentioning

confidence: 99%

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

2020

View full text Add to dashboard Cite

Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant inhibition of cancer cell proliferation by modulating multiple signaling pathways. First of all, they act as histone deacetylase (HDAC) inhibitors (HDIs), being involved in the epigenetic regulation of gene expression. Afterward, VPA is shown to induce apoptosis and cell differentiation, as well as regulate Notch signaling. Moreover, it up-regulates the expression of certain G protein-coupled receptors (GPCRs), which are involved in various signaling pathways associated with cancer. As a consequence, some pre-clinical and clinical trials were carried out to estimate anticancer effectiveness of VPA, in monotherapy and in new drug combinations, while other SCFAs were tested in pre-clinical studies. The present manuscript summarizes the most important information from the literature about their potent anticancer activities to show some future perspectives related to epigenetic therapy.

show abstract

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Cited by 40 publications

References 59 publications

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Structure‐cytotoxicity relationship for apoptotic inducers organotin(IV) derivatives of mandelic acid and L‐proline and their mixed ligand complexes having enhanced cytotoxicity

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

Contact Info

Product

Resources

About

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Cited by 40 publications

References 59 publications

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Structure‐cytotoxicity relationship for apoptotic inducers organotin(IV) derivatives of mandelic acid and L‐proline and their mixed ligand complexes having enhanced cytotoxicity

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

Contact Info

Product

Resources

About

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects