Alterations in the mitochondrial responses to PENAO as a mechanism of resistance in ovarian cancer cells

Decollogne, Stéphanie; Joshi, Swapna; Chung, Sylvia A.; Luk, Peter P.; Yeo, Reichelle X.; Nixdorf, Sheri; Fedier, André; Heinzelmann‐Schwarz, Viola; Hogg, Philip J.; Dilda, Pierre J.

doi:10.1016/j.ygyno.2015.06.018

Cited by 19 publications

(18 citation statements)

References 36 publications

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“…Inactivation of ANT causes proliferation arrest, ATP depletion, superoxide level increase, mitochondrial depolarization and apoptosis in proliferating endothelial and tumour cells. Similar to our study in diverse STS and OS cell lines, PENAO showed anti-proliferation with low micromolar IC 50 s in epithelial cancer cells [45,51]. A Phase I/IIa dose escalation study of PENAO in patients with solid tumours refractory to standard therapy is currently recruiting.…”

Section: Discussionsupporting

confidence: 81%

“…4-(N-(S-penicillaminylacetyl) amino) phenylarsonous acid (PENAO), a second generation synthetic trivalent organic-arsenical compound created in our laboratory, intrinsically blocks cell proliferation in vitro and tumour growth in vivo by perturbing mitochondrial function [45,[49][50][51]. PENAO's trivalent arsenical moiety cross-links unpaired cysteine residues Cys 57 and Cys 257 located on the peptide loop of ANT that protrude into the matrix [39].…”

Section: Research Papermentioning

confidence: 99%

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The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

et al. 2020

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Our group previously demonstrated that sarcoma cell lines were insensitive to epidermal growth factor receptor (EGFR) inhibitor gefitinib monotherapy. PENAO, an anti-tumour metabolic compound created in our laboratory, is currently in clinical trials. Considering the positive regulation of tumour energy production by both the EGFR signalling and tumour metabolism pathways, this study aimed to investigate the effect and mechanisms of combination therapy using gefitinib and PENAO in sarcoma cell lines in vitro and in vivo. PENAO monotherapy reduced proliferation in 12 sarcoma cell lines. Combining gefitinib and PENAO resulted in synergistic inhibition in both a time-and dosedependent manner in 3 sarcoma cell lines with less prominent monotherapy effects. Combined treatment significantly enhanced cell death and perturbed mitochondrial function. In vivo combination therapy with PENAO and gefitinib was non-toxic to mice and significantly delayed tumour growth and prolonged survival. At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice. The survival curves also showed significant difference across and between groups. The combination of PENAO and gefitinib in vitro and in vivo, shows promise as a treatment pathway in this poor outcome tumour.

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Section: Discussionsupporting

confidence: 81%

Section: Research Papermentioning

confidence: 99%

The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

et al. 2020

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“…Heme consumption might participate in endometrial carcinogenesis, being associated with a moderate increase in EC risk (46). Targeting this pathway is currently being tested for the treatment of ovarian cancer and other solid tumors using a new drug, 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), acting through the induction of heme degradation by heme oxygenase-1 (47,48).…”

Section: Discussionmentioning

confidence: 99%

Identification of metabolomic biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women

Audet-Delage

Villeneuve

Grégoire

et al. 2019

Drug Metabolism and Pharmacokinetics

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“…We found that DIPG primary cultures express high levels of ANT2 protein compared with nearly undetectable levels in NHAs, and that it serves as a potential therapeutic target for this aggressive paediatric disease. The over-expression of ANT2 in particular results in an anti-apoptotic role signal in cancer cells [ 17 – 19 ]. Pharmacological inhibition of this mitochondrial protein with PENAO led to low micromolar efficacy in a panel of primary neurosphere-forming DIPG cells.…”

Section: Discussionmentioning

confidence: 99%

Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

et al. 2018

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Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted.

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Alterations in the mitochondrial responses to PENAO as a mechanism of resistance in ovarian cancer cells

Cited by 19 publications

References 36 publications

The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas

Identification of metabolomic biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women

Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

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