Phosphaplatins, next generation platinum antitumor agents: A paradigm shift in designing and defining molecular targets

Moghaddas, Shadi; Majmudar, Pooja; Marin, Roberto; Dezvareh, Homa; Qi, Chunyan; Soans, Eroica; Bose, Rathindra N.

doi:10.1016/j.ica.2012.05.040

Cited by 22 publications

(40 citation statements)

References 25 publications

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“…In fact, R,R-isomer of pyrodach-2 exhibited excellent in vivo efficacy against cisplatin-resistant human ovarian cells (OVCAR-10). 18 As reported here and earlier, both cisplatin-sensitive and -resistant human ovarian cells, exhibit similar T/C an ILS values. The engagement of the extrinsic apoptotic pathway, along with the lack of potential DNA repairbased resistance, makes these compounds attractive alternatives to platinum-based therapies currently in use.…”

Section: Discussionsupporting

confidence: 82%

“…Notably, NLCK values of 1.6 and above are considered to be highly active anticancer compound for less than 5 days treatment. These data are consistent with similar efficacies for both 10 mg/kg RRD2 and 10 mg/kg RRD4 18 . Taken together, these data indicate both RRD2 and RRD4 exhibited superior efficacy compared to cisplatin.…”

Section: Selection Of Vehicle For Efficacy Studies Based On Stabilitysupporting

confidence: 86%

“…18 The requirement of the DNA repair genes following treatment of yeast cells with RRD2 and RRD4 complexes, which are largely responsible for creating cisplatin resistance, were examined in genome-wide assays. To analyze the genome-wide effects of D2 and D4, we used HIPHOP to screen 1200 essential genes as heterozygote deletion mutants (reducing functional gene dose from 2 to 1), and 4800 non-essential genes as complete deletions (reducing functional gene dose Table 1 show the levels of sensitivity for strains deficient in expression of genes involved in DNA repair.…”

Section: Phosphaplatin Complexes Increase Levels Of Apoptosis In Vitromentioning

confidence: 99%

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Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

et al. 2015

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Phosphaplatins, platinum(II) and platinum(IV) complexes coordinated to a pyrophosphate moiety, exhibit excellent antitumor activities against a variety of cancers. To determine whether phosphaplatins trigger resistance to treatment by engaging DNA damage repair genes, a yeast genome-wide fitness assay was used. Treatment of yeast cells with pyrodach-2 (D2) or pyrodach-4 (D4) revealed no particular sensitivity to nucleotide excision repair, homologous recombination repair, or postreplication repair when compared with platin control compounds. Also, TNF receptor superfamily member 6 (FAS) protein was overexpressed in phosphaplatin-treated ovarian tumor cells, and platinum colocalized with FAS protein in lipid rafts. An overactivation of sphingomyelinase (ASMase) was noted in the treated cells, indicating participation of an extrinsic apoptotic mechanism due to increased ceramide release. Our results indicate that DNA is not the target of phosphaplatins and accordingly, that phosphaplatins might not cause resistance to treatment. Activation of ASMase and FAS along with the colocalization of platinum with FAS in lipid rafts support an extrinsic apoptotic signaling mechanism that is mediated by phosphaplatins.

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Section: Discussionsupporting

confidence: 82%

Section: Selection Of Vehicle For Efficacy Studies Based On Stabilitysupporting

confidence: 86%

Section: Phosphaplatin Complexes Increase Levels Of Apoptosis In Vitromentioning

confidence: 99%

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Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

et al. 2015

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“…297 The authors accumulate evidence highlighting the distinctions between the biological effects of the classical platinum drugs and the pyrophosphate complexes, but no mechanistic model has yet to be proposed. 298 …”

Section: Platinum(ii) Compounds With a Mechanism Of Action Differementioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive.

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“…The limited doses that can be administered to patients also means that tumors can develop resistance 5 . As such, new drugs continue to be developed to improve the side effect profile and overcome acquired resistance, like phenanthriplatin 6 and phosphaplatin 7 .…”

Section: Introductionmentioning

confidence: 99%

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

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Johnson

Sutcliffe

et al. 2014

JoVE

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Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1 H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand. Video LinkThe video component of this article can be found at

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Phosphaplatins, next generation platinum antitumor agents: A paradigm shift in designing and defining molecular targets

Cited by 22 publications

References 25 publications

Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

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