Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

Dhar, Shanta; Lippard, Stephen J.

doi:10.1073/pnas.0912276106

Cited by 343 publications

(249 citation statements)

References 39 publications

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…DCA had no additive effect in the two non-small-cell lung cancer cell lines A549 and H719 with paclitaxel, etoposide or cisplatin. However, mitaplatin, a compound where two DCA molecules were appended to the axial positions of a six-coordinate Pt(IV) centre, showed promising activity [54,55]. Our results demonstrate that DCA inhibits growth of the chemoresistant UMC-11 cell line and sensitises the cells to carboplatin, JM118 and oxoplatin at concentrations that can be achieved in vivo [56].…”

Section: Discussionmentioning

confidence: 67%

See 1 more Smart Citation

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

et al. 2011

View full text Add to dashboard Cite

The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.

show abstract

Section: Discussionmentioning

confidence: 67%

“…The effi cacy of platinum complexes is expected to be improved further in combination with dichloroacetate (DCA), which targets pyruvate dehydrogenase kinase. Thus, the additive effect of this compound on the cytotoxicity of the platinum drugs was furthermore investigated [21].…”

Section: Introductionmentioning

confidence: 99%

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The cellular accumulation of platinum was determined as previously described (27,28), with some modifications. The detailed procedure is described in the SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Park

Wilson

Song

et al. 2012

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

Self Cite

283

311

View full text Add to dashboard Cite

Monofunctional platinum(II) complexes of general formula cis-[Pt(NH 3 ) 2 (N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH 3 ) 2 (phenanthridine)Cl]NO 3 , which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. (Fig. 1), are currently among the most effective chemotherapies in clinical use for the treatment of cancers (1). These Pt-based anticancer agents typically form bifunctional intra-and interstrand DNA cross-links through covalent bonds with purine nucleobases. These cross-links inhibit transcription and result in cell death (2, 3). Platinum-based drugs are limited by side effects and poor activity in certain types of cancer resulting from acquired or intrinsic resistance (1-3). These limitations evoke a need for new platinum-based chemotherapeutics with novel mechanisms of action.One approach that we have used to circumvent the shortcomings of classic bifunctional platinum-based drugs has been to revisit cationic, monofunctional platinum complexes previously demonstrated to display significant anticancer activity in animal tumor models (4). In contrast to monofunctional platinum(II) compounds, such as [Pt(dien)Cl] + (dien = diethylenetriamine) (5) and [Pt(NH 3 ) 3 Cl] + (6), which early work proved to be inactive, the compound pyriplatin [cis-diamminepyridinechloroplatinum(II)] (Fig. 1) and several of its analogs have significant antineoplastic activity. Moreover, the profile of cellular response to thes...

show abstract

“…12 Silver and gold complexes are found to be promising alternatives to old anticancer agents, showing activity on tumors that have developed resistance. 13 The serious limitations of cancer treatments have prompted many researchers to develop alternative strategies based on different metals, ligands, and mechanisms for cancer.…”

mentioning

confidence: 99%

Two new coordination polymers containing dicyanidoargentate(I) and dicyanidoaurate(I): synthesis and characterization, and a detailed in vitro investigation of their anticancer activities on some cancer cell lines

Aydın¹,

Karadağ²,

Teki̇n³

et al. 2015

Turk J Chem

View full text Add to dashboard Cite

Two novel cyanido-bridged bimetallic polymeric complexes, [Ni(edbea) to the anticancer drug 5FU against the cancer cell lines tested. The antiproliferative and cytotoxic activities of C1 and C2 were significantly lower than those of free anions, indicating that the extreme cytotoxicity of free anions decreased to safe levels in C1 and C2 . In conclusion, the results show that these novel compounds possess anticancer activities.

show abstract

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

Abstract: cancer therapy ͉ DNA damage ͉ mitochondrion ͉ platinum ͉ Warburg effect

Cited by 343 publications

References 39 publications

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Two new coordination polymers containing dicyanidoargentate(I) and dicyanidoaurate(I): synthesis and characterization, and a detailed in vitro investigation of their anticancer activities on some cancer cell lines

Contact Info

Product

Resources

About