Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Calandrini, Vania; Nguyen, Trung Hai; Arnesano, Fabio; Galliani, Angela; Ippoliti, Emiliano; Carloni, Paolo; Natile, Giovanni

doi:10.1002/chem.201402834

Cited by 18 publications

(15 citation statements)

References 76 publications

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“…The cohort of Tranilast-sensitive transcripts included ATOX1, COX17, and SOD1 that normally supply Cu to biosynthetic, mitochondrial, and anti-oxidant pathways, respectively [31][32][33]. Pt binding to ATOX1, COX17, and SOD1 has been documented [34,[39][40][41]. Moreover, an increase in SOD1 and ATOX1 expression has been suggested to confer cisplatin resistance to tumor cells [34,42].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Mariniello

Petruzzelli

Wanderlingh

et al. 2020

Cancers

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Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Mariniello

Petruzzelli

Wanderlingh

et al. 2020

Cancers

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“…Several groups have documented direct binding of cDDP to ATOX1 in solution 30, 53 and in cells 31 . Drosophila ATOX1 knockout cells were found to be resistant to 1 mM cDDP 33 , while ATOX1 −/− MEFs had a 1.5-fold increase in IC 50 32 .…”

Section: Discussionmentioning

confidence: 99%

“…cDDP also binds the Cu chaperone COX17 in solution, and COX17 mediates mitochondrial delivery which, in turn, affects cDDP sensitivity through non-DNA related apoptosis pathways 28 . cDDP has also been shown to bind ATOX1 in solution 29, 30 and in cells 31 . ATOX1 knockout mutations in both Drosophila and MEFs engendered resistance to cDDP 32, 33 .…”

Section: Introductionmentioning

confidence: 99%

Copper transporters and chaperones CTR1, CTR2, ATOX1, and CCS as determinants of cisplatin sensitivity

et al. 2016

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The development of resistance to cisplatin (cDDP) is commonly accompanied by reduced drug uptake or increased efflux. Previous studies in yeast and murine embryonic fibroblasts have reported that the copper (Cu) transporters and chaperones participate in the uptake, efflux, and intracellular distribution of cDDP. However, there is conflicting data from studies in human cells. We used CRISPR-Cas9 genome editing to individually knock out the human copper transporters CTR1 and CTR2 and the copper chaperones ATOX1 and CCS. Isogenic knockout cell lines were generated in both human HEK-293T and ovarian carcinoma OVCAR8 cells. All knockout cell lines had slowed growth compared to parental cells, small changes in basal Cu levels, and varying sensitivities to Cu depending on the gene targeted. However, all of the knockouts demonstrated only modest 2 to 5-fold changes in cDDP sensitivity that did not differ from the range of sensitivities of 10 wild type clones grown from the same parental cell population. We conclude that, under basal conditions, loss of CTR1, CTR2, ATOX1, or CCS does not produce a change in cisplatin sensitivity that exceeds the variance found within the parental population, suggesting that they are not essential to the mechanism by which cDDP enters these cell lines and is transported to the nucleus.

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“…A recent review reports CPMD/MM applications that address this issue. 169 The method has also recently provided valuable insights on DNA damage 16,[170][171][172][173][174][175] and on the binding of anticancer drugs to DNA [176][177][178][179][180] or to the copper transport protein, [181][182][183] which is supposed to function as a transporter of cisplatin.…”

Section: Applications To Biological Systemsmentioning

confidence: 99%

Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

Dreyer¹,

Brancato²,

Ippoliti³

et al. 2016

Theoretical and Computational Chemistry Series

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Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Cited by 18 publications

References 76 publications

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Copper transporters and chaperones CTR1, CTR2, ATOX1, and CCS as determinants of cisplatin sensitivity

Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

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