Effects of Monofunctional Platinum Agents on Bacterial Growth: A Retrospective Study

Johnstone, Timothy C.; Alexander, Sarah M.; Lin, Wenhan; Lippard, Stephen J.

doi:10.1021/ja411742c

Cited by 81 publications

(73 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The interaction of phenanthriplatin with DNA in Escherichia coli provided further evidence to support the hypothesis that DNA is the ultimate biological target of this anti-cancer agent (figure 4). Unlike monofunctional platinum(II) complexes with little or no anti-cancer activity, phenanthriplatin was able to replicate the filamentous growth morphology that cisplatin induces in E. coli [40]. This phenotype arises from induction of the bacterial SOS response as a result of DNA damage.…”

Section: (B) Phenanthriplatin: a Potent Monofunctional Complexmentioning

confidence: 98%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

Self Cite

View full text Add to dashboard Cite

Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.

show abstract

Section: (B) Phenanthriplatin: a Potent Monofunctional Complexmentioning

confidence: 98%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…275,276 Studies with Escherichia coli resembling those conducted by Rosenberg, showed that akin to cisplatin treatment, phenanthriplatin induced filamentous cell growth. 277 Monofunctional platinum(II) complexes with little biological activity in cultured cancer cells were not able to replicate this result. Phenanthriplatin-mediated filamentous E. coli growth resulted from the bacterial SOS response, indicative of DNA damage.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Phenanthriplatin maintains a spectrum of activity that is distinct from that of any other platinum agent tested in the NCI60 human tumor cell line anticancer drug screen and is 7-40 times more potent than cisplatin. The complex interacts covalently with DNA, presumably at the nucleophilic N7 position of guanine, and inhibits transcription by RNA polymerase II (18,20,21). Phenanthriplatin contains a center of chirality and can therefore form diastereomeric adducts with DNA.…”

Section: Significancementioning

confidence: 99%

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage

Gregory

Park

Johnstone

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η− cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.cancer therapy | monofunctional platinum drug candidates | pol eta | X-ray crystallography

show abstract

Effects of Monofunctional Platinum Agents on Bacterial Growth: A Retrospective Study

Cited by 81 publications

References 16 publications

Third row transition metals for the treatment of cancer

Third row transition metals for the treatment of cancer

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

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage

Contact Info

Product

Resources

About