Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting

Lovejoy, Katherine S.; Lippard, Stephen J.

doi:10.1039/b913896j

Cited by 207 publications

(141 citation statements)

References 82 publications

(122 reference statements)

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“…To overcome the resistance that gives rise to decreased efficacy of platinum therapy, compounds with alternative, nonclassical molecular structures are being investigated (16). Monofunctional platinum compounds differ from the clinically used bifunctional species in that they form only one covalent bond to DNA (17).…”

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.

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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

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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.

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“…isplatin is a platinum(II) containing chemotherapy drug proven to be an effective treatment for several types of solid tumors [1][2][3]. However, a large number of cancer patients develop cisplatin resistance and a number of side effects are commonly reported [1][2][3].…”

mentioning

confidence: 99%

“…However, a large number of cancer patients develop cisplatin resistance and a number of side effects are commonly reported [1][2][3]. For this reason, considerable efforts have been made to create new effective anticancer metallodrugs [4][5][6][7].…”

mentioning

confidence: 99%

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

Lee

Jayathilaka

Gupta

et al. 2012

J. Am. Soc. Mass Spectrom.

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Stimulated by the interest in developing gold compounds for treating cancer, gold ionangiotensin peptide interactions are investigated by mass spectrometry. Under the experimental conditions used, the majority of gold ion-angiotensin peptide complexes contain gold in the oxidation states I and III. Both ESI-MS and MALDI-TOF MS detect singly/multiply charged ions for mononuclear/multinuclear gold-attached peptides, which are represented as [peptide+a Au (I)+b Au(III)+(e -a -3b) H] e+ , where a,b≥0 and e is charge. ESI-MS data shows singly/multiply charged ions of Au(I)-peptide and Au(III)-peptide complexes. This study reveals that MALDI-TOF MS mainly detects singly charged Au(I)-peptide complexes, presumably due to the ionization process. The electrons in the MALDI plume seem to efficiently reduce Au(III) to Au(I). MALDI also tends to enhance the higher polymeric forms of gold-peptide complexes regardless of the laser power used. Collision-induced dissociation experiments of the mononuclear and dinuclear gold-attached peptide ions for angiotensin peptides show that the gold ion (a soft acid) binding sites are in the vicinity of Cys (a soft ligand), His (a major anchor of peptide for metal ion chelation), and the basic residue Arg. Data also suggests that the abundance of gold-attached peptides increases with higher gold concentration until saturation, after which an increase in gold ion concentration leads to the aggregation and/or precipitation of gold-bound peptides.

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“…22,23 The most widely used metal-based anticancer drug, cisplatin, [24][25][26] has been encapsulated in various hosts to reduce the severe side effects associated with this treatment. 27,28 The field is now entering a new era in which applications such as micro-reactors or transporters are leading to new perspectives for metalla-cages. 29 Macrophages represent a type of white blood cell that digests dead cell debris, xenobiotics, foreign substances, and cancer cells in a process called phagocytosis.…”

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confidence: 99%

Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages

Dubey

Park

Kwon

et al. 2015

IJN

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Three new large hexanuclear metalla-prisms 9 – 11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru 2 ( p - i PrC 6 H 4 Me) 2 ( OO ∩ OO )][CF 3 SO 3 ] 2 ( OO ∩ OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1 , 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2 , and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3 ), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5 ) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by 1 H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORAC PE value (1.30±0.020). Ellagic acid ( 5 ) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC 50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid ( 5 ) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein in macrophages.

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Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting

Cited by 207 publications

References 82 publications

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

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

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages

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