Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins

Pisa, Rudolf; Cupido, Tommaso; Steinman, Jonathan B.; Jones, Natalie H.; Kapoor, Tarun M.

doi:10.1016/j.chembiol.2019.06.001

“…The superimposition of compounds 31 and 32 from crystal structures showed the core, phenyl(1H-1,2,4-triazol-1-yl)methanone, occupied the same site and the substituents on 1,2,4-triazol ring were facing the opposite direction (Figure 12D). [144]. J o u r n a l P r e -p r o o f…”

Section: Spastinmentioning

confidence: 99%

AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Zhang

¹

,

Li

²

,

Cheng

³

et al. 2021

European Journal of Medicinal Chemistry

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“…Therefore, gaining an understanding of how cancer can become resistant is of significant importance at both the preclinical and clinical stages of drug development. Additionally, resistance pathways can often allude to the underlying mechanism or molecular target of the drug candidate . Our lab has been studying the biological and anticancer activity of rhenium‐based compounds, in part because they are not cross‐resistant with the conventional and widely used platinum‐based drugs .…”

Section: Resultsmentioning

confidence: 99%

“…Additionally,r esistance pathways can often allude to the underlying mechanism or molecular target of the drug candidate. [14][15][16][17][18][19][20] Our lab has been studying the biological and anticancer activity of rhenium-based compounds,i np art because they are not cross-resistant with the conventional and widely used platinum-based drugs. [12,13,[21][22][23] Among the com-pounds that we have investigated, TRIP (Scheme 1) was found to be equally as effective as cisplatin in the A2780 ovarian cancer cell line.F urthermore,T RIP operates via ad istinct mechanism of action by inducing ER stress, activating the UPR pathway,a nd subsequently initiating apoptosis.B yc ontrast, the platinum-based drugs form covalent adducts on DNAa nd inhibit transcription.…”

Section: Development and Characteristics Of The A2780 Trip-resistant mentioning

confidence: 99%

“…Gaining an understanding of how ovarian cancer responds to prolonged TRIP treatment will be important for developing long‐term therapeutic strategies. Furthermore, cellular resistance pathways often convey information regarding the mechanism of action of a drug candidate . To identify the resistance mechanisms that may attenuate the activity of TRIP, in this study we developed a TRIP‐resistant A2780 ovarian cancer cell line, which we call A2780TR.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore,c ellular resistance pathways often convey information regarding the mechanism of action of ad rug candidate. [14][15][16][17] To identify the resistance mechanisms that may attenuate the activity of TRIP,inthis study we developed aTRIP-resistant A2780 ovarian cancer cell line,which we call A2780TR. These efforts have identified that TRIP resistance arises largely from increased expression of the ABCB1 transporter,o rP -glycoprotein (Pgp), and the MT1E gene, which encodes for metal-binding metallothioneins.W eh ave also tested the efficacyo fo ther anticancer agents,i ncluding rhenium-based complexes,common organic chemotherapeutics,a nd well-known metal-based anticancer drugs,i nt his TRIP-resistant cell line,t od etermine the extent of cross resistance between these different compounds.T ogether, these results highlight the unexpected role of ABC transporters,w hich are generally known to act on organic substrates,todetoxify metal-based anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Marker

¹

,

King

²

,

Swanda

³

et al. 2020

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Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3(dmphen)(ptolICN)]+, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

show abstract

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Marker

¹

,

King

²

,

Swanda

³

et al. 2020

View full text Add to dashboard Cite

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)3(dmphen)(ptolICN)]+, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.

show abstract

Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins

Cited by 20 publications

References 47 publications

AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

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