Mitaplatin Increases Sensitivity of Tumor Cells to Cisplatin by Inducing Mitochondrial Dysfunction

Xue, Xue; You, Song; Zhang, Qiang; Wu, Yan; Zou, Guo Zhang; Wang, Paul; Zhao, Yu; Xu, Yan; Jia, Lee; Zhang, Xiaoning; Lü, Xing

doi:10.1021/mp200571k

Cited by 85 publications

(54 citation statements)

References 43 publications

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“…Subsequent work showed that this mechanism of action was able to overcome cisplatin-resistance in human epidermoid adenocarcinoma and hepatoma cancer cells. 365 Detailed biophysical studies investigating the aqueous chemistry of mitaplatin and related platinum(IV) complexes with axial haloacetate ligands, found that, contrary to the typical dogma that platinum(IV) prodrugs are inert to ligand substitution, these the axial ligands of these complexes can be substituted for hydroxide under biologically relevant conditions. 366 Isotopic labelling studies revealed that the hydrolysis proceeds via the attack of a hydroxide ion on the platinum(IV) center, and not at the carbonyl of the haloacetate.…”

Section: Dual-threat Platinum(iv) Prodrugs That Release Classical mentioning

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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Section: Dual-threat Platinum(iv) Prodrugs That Release Classical mentioning

confidence: 99%

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

2016

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“…The expected effects of DCA, such as decreased glucose uptake and inhibition of PDK, were observed. 131 Synergism of DCA with commonly used platinum(II) anticancer drugs has also been noted. 132–134 The concentrations of DCA required to see such effects, however, is between 2 to 10 mM, substantially higher than the low μM concentrations provided by mitaplatin.…”

Section: Platinum(iv) Anticancer Complexesmentioning

confidence: 99%

“…Later studies by another research group investigated the efficacy of mitaplatin in cisplatin-resistant cell lines. 131 Mitaplatin was more effective than cisplatin in resistant cell lines. The expected effects of DCA, such as decreased glucose uptake and inhibition of PDK, were observed.…”

Section: Platinum(iv) Anticancer Complexesmentioning

confidence: 99%

Monofunctional and Higher-Valent Platinum Anticancer Agents

2013

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Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called “non-traditional” platinum(II) and platinum(IV) compounds that violate the structure-activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with an historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo.

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“…Within tumor cell sub populations, the higher the Δψ m , the more likely the contribution to tumor progression and expansion [40]. In human epidermoid adenocarcinoma and hepatoma cancer cells, a higher Δψ m defines resistance to cisplatin [41]. As the Δψ m increases, intracellular cationic entities will increasingly permeate the mitochondria.…”

Section: Malignant Mitochondria (The Tumor Signature)mentioning

confidence: 99%

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

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The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein-protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.The mitochondrion holds importance among cellular organelles in consideration of selective anticancer therapy because it is the nexus for propagating malignant transformation and controls cell death. The mitochondrion is a universal target in all cancer cells, and new information about functional and structural differences between healthy and malignant cells continues to emerge [1]. Peptides that specifically target malignant mitochondria offer advantages of low toxicity, high specificity and generally increase the range of interactions that are difficult to target with small molecules (e.g., protein-protein, protein-lipid and protein-DNA) [2]. However, the benefits of peptides are offset by difficulties in delivery, such as degradation by proteases and rapid clearance. As such, the delivery of peptide/ protein therapeutics is almost exclusively by the parenteral route, but the status quo is actively being challenged by broad efforts (e.g., liposomes, microparticles, nanoparticles, 'smart' polymers, hydrogels and chemical modifications to the peptide/protein) to achieve more convenient routes of administration (i.e., oral, nasal and transdermal) and improved pharmacokinetics [3][4][5]. However, peptides, in many cases, are far from passive in the delivery process and through the maze that is drug delivery (from route of administration to perhaps a target residing within a specific organelle), peptides are employed as the vehicle, homing motif and trans-/intra-cellular passport [6].There is an emerging view in cancer therapy that the way in which a cancer cell dies (i.e., immunogenic cell death) is important for a durable response [7]. However, traditional chemo therapy and immune response are in conflict because chemotherapy (e.g., DNA-© 2012 Future Science Ltd * Author for correspondence: Tel.: +1 801 581 7120 Fax: +1 801 585 3614 carol.lim@pharm.utah.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript....

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Mitaplatin Increases Sensitivity of Tumor Cells to Cisplatin by Inducing Mitochondrial Dysfunction

Cited by 85 publications

References 43 publications

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

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

Monofunctional and Higher-Valent Platinum Anticancer Agents

Targeting Malignant Mitochondria With Therapeutic Peptides

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