Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours

Propper, David; Braybrooke, Jeremy; Taylor, Doris J.; Lodi, Raffaele; Styles, Peter; Cramer, Jeffrey A.; Collins, Wanda; Levitt, N C; Talbot, Denis; Ganesan, Trivadi S.; Harris, Adrian L.

doi:10.1023/a:1008336904585

Cited by 111 publications

(80 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that its selective toxicity to tumor cells is mediated by binding to mortalin and reactivation of p53 function [31]. Although a phase I trial of MKT-077 with chemoresistant solid tumors failed because of renal toxicity [32], there remains a possibility for using the drug in mortalin-expressing tumors. Deocaris et al [33] have reported that in tumor cells with elevated mortalin expression, low doses of MKT-077 are sufficient to induce senescence and might prevent renal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Mortalin is a prognostic factor of gastric cancer with normal p53 function

et al. 2013

View full text Add to dashboard Cite

Background Mortalin is a heat-non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53. Methods Expression of mortalin and p53 was examined by immunohistochemical staining of 182 clinical samples of gastric cancer. Results Mortalin-positive and aberrant p53-positive tumors were found in 75.2 and 49.5 % of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (P \ 0.01, P \ 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.035). Moreover, in tumors with normal p53 function, mortalinpositive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.017). Conclusions Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53.

show abstract

Section: Discussionmentioning

confidence: 99%

Mortalin is a prognostic factor of gastric cancer with normal p53 function

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Several experimental anti-cancer drugs, such as ceramide [46] , CD437 [47] , and MKT077 [48] , and clinically approved anti-cancer drugs, such as etoposide [49] , paclitaxel [50] , and vinorelbine [51] , induce apoptosis via mitochondria dysfunction. Furthermore, determining of pathophysiological differences of mitochondria between cancer cells and normal cells, will improve the selectivity of mitochondria-targeted anti-cancer agents.…”

Section: Mitochondrial Membrane Potentialmentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer stem cells

Song¹,

Jeong²,

Jeong³

et al. 2015

WJSC

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are maintained by their somatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.

show abstract

“…20,22,24−26 Based on these observations, MKT-077 advanced to a phase I clinical study as an anti-cancer agent; however, progress was halted due to its nephrotoxicity in a subset of patients. 27,28 Renal damage was likely exacerbated by the dramatic accumulation of MKT-077 in the kidney, as shown by whole animal imaging and pharmacodynamic studies. 29 Moreover, these same studies confirmed that MKT-077 does not cross the BBB, 30 blunting any potential use in treating or studying neurodegenerative diseases.…”

mentioning

confidence: 99%

Synthesis and Initial Evaluation of YM-08, a Blood-Brain Barrier Permeable Derivative of the Heat Shock Protein 70 (Hsp70) Inhibitor MKT-077, Which Reduces Tau Levels

Miyata

Lee

et al. 2013

ACS Chem. Neurosci.

111

117

View full text Add to dashboard Cite

The molecular chaperone, heat shock protein 70 (Hsp70), is an emerging drug target for treating neurodegenerative tauopathies. We recently found that one promising Hsp70 inhibitor, MKT-077, reduces tau levels in cellular models. However, MKT-077 does not penetrate the blood-brain barrier (BBB), limiting its use as either a clinical candidate or probe for exploring Hsp70 as a drug target in the central nervous system (CNS). We hypothesized that replacing the cationic pyridinium moiety in MKT-077 with a neutral pyridine might improve its clogP and enhance its BBB penetrance. To test this idea, we designed and synthesized YM-08, a neutral analogue of MKT-077. Like the parent compound, YM-08 bound to Hsp70 in vitro and reduced phosphorylated tau levels in cultured brain slices. Pharmacokinetic evaluation in CD1 mice showed that YM-08 crossed the BBB and maintained a brain/plasma (B/P) value of ∼0.25 for at least 18 h. Together, these studies suggest that YM-08 is a promising scaffold for the development of Hsp70 inhibitors suitable for use in the CNS.

show abstract

Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours

Cited by 111 publications

References 6 publications

Mortalin is a prognostic factor of gastric cancer with normal p53 function

Mortalin is a prognostic factor of gastric cancer with normal p53 function

Mitochondria as therapeutic targets for cancer stem cells

Synthesis and Initial Evaluation of YM-08, a Blood-Brain Barrier Permeable Derivative of the Heat Shock Protein 70 (Hsp70) Inhibitor MKT-077, Which Reduces Tau Levels

Contact Info

Product

Resources

About