Prediction and identification of synergistic compound combinations against pancreatic cancer cells

KalantarMotamedi, Yasaman; Choi, Ran Joo; Koh, Siang-Boon; Bramhall, Jo L.; Fan, Tai-Ping; Bender, Andreas

doi:10.1016/j.isci.2021.103080

Cited by 3 publications

(4 citation statements)

References 80 publications

(109 reference statements)

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“…Drug combinations are a cornerstone for cancer therapy [28] because combining two drugs with different mechanisms of action and at lower doses may overcome drug resistance and lead to fewer side effects [29]. Our data suggest that PP and GEM may have different modus opperandi and we speculated that PP may improve the anti-cancer activity of GEM in PDAC patients.…”

Section: Pp Enhances the Effects Of Gemcitabine On Dna Damage And Pda...mentioning

confidence: 79%

“…Combination therapies have proven to be an effective strategy for the management of PDAC. Indeed combining low doses of drugs with dinstict mechanisms of action may overcome drug resistance and lead to an increased efficacy without or with minimal side effects [29]. Most anti-PDAC combination regimens are centered on GEM because it is the only FDA-approved monotherapy and several of these including the FDA-approved GEM plus nab-paclitaxel have improved patient survival [50].…”

Section: Discussionmentioning

confidence: 99%

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Pyrvinium Pamoate Enhances the Anti-cancer Activities of Gemcitabine in Pancreatic Cancer

Serala,

Bai,

Prince

2024

Preprint

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Pancreatic cancer is an intractable disease with the worst prognosis of all cancers. The currently used treatment regimens do not significantly impact patient survival, and therefore, effective treatment strategies are urgently needed. Drug repurposing, which identifies new indications for existing and approved drugs, has proven to be a promising approach to anti-cancer drug discovery. Indeed the antihelmintic drug, pyrvinium pamoate has shown promise as an anti-pancreatic cancer drug, but to date, the inhibition of mitochondrial function is the only mechanism of action described in pancreatic cancer. This study showed, using pancreatic cancer 2D cell cultures and 3D spheroids, that pyrvinium pamoate exhibited short- and long-term cytotoxicity, inhibited epithelial-to-mesenchymal transition and cell invasion and migration. Mechanistically, pyrvinium pamoate induced DNA damage, inhibited the PI3K/AKT cell survival pathway, and triggered cell cycle arrests, as well as apoptotic and autophagic cell death. Importantly, pyrvinium pamoate acted synergistically with the first-line drug, gemcitabine in 2D and 3D pancreatic cancer cell culture models. This study provided evidence that pyrvinium pamoate is effective as a single agent and in combination with gemcitabine for the treatment of pancreatic cancer.

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Section: Pp Enhances the Effects Of Gemcitabine On Dna Damage And Pda...mentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Pyrvinium Pamoate Enhances the Anti-cancer Activities of Gemcitabine in Pancreatic Cancer

Serala,

Bai,

Prince

2024

Preprint

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“…Huh7-4P cells were treated with increasing doses of combination drugs in a 7 × 7 concentration checkerboard format [ 46 , 47 ]. To fully understand the synergy of the drug combination, avoid the calculation deviation caused by a certain calculation mode, HSA, Bliss, Loewe and ZIP synergy metrics were compared for combinations and single agents calculated with the SynergyFinder tool [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibiting the transcription and replication of Ebola viruses by disrupting the nucleoprotein and VP30 protein interaction with small molecules

et al. 2023

Acta Pharmacol Sin

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Ebola virus (EBOV) causes hemorrhagic fever in humans with high morbidity and fatality. Although over 45 years have passed since the first EBOV outbreak, small molecule drugs are not yet available. Ebola viral protein VP30 is a unique RNA synthesis cofactor, and the VP30/NP interaction plays a critical role in initiating the transcription and propagation of EBOV. Here, we designed a high-throughput screening technique based on a competitive binding assay to bind VP30 between an NP-derived peptide and a chemical compound. By screening a library of 8004 compounds, we obtained two lead compounds, Embelin and Kobe2602. The binding of these compounds to the VP30-NP interface was validated by dose-dependent competitive binding assay, surface plasmon resonance, and thermal shift assay. Moreover, the compounds were confirmed to inhibit the transcription and replication of the Ebola genome by a minigenome assay. Similar results were obtained for their two respective analogs (8-gingerol and Kobe0065). Interestingly, these two structurally different molecules exhibit synergistic binding to the VP30/NP interface. The antiviral efficacy (EC 50 ) increased from 1 μM by Kobe0065 alone to 351 nM when Kobe0065 and Embelin were combined in a 4:1 ratio. The synergistic anti-EBOV effect provides a strong incentive for further developing these lead compounds in future studies.

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“…On the cellular level, gene expression data for drug combination discovery has been used, e.g., in pancreatic cancer drug discovery, 40 which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Compounds suggested as combination agents with the standard therapy gemcitabine, based on the best-performing scoring system, showed on average 2.82–5.18 times higher synergies compared to compounds that were predicted to be active as single agents.…”

Section: Transcriptomics Datamentioning

confidence: 99%

Using Transcriptomics and Cell Morphology Data in Drug Discovery: The Long Road to Practice

Pruteanu

Bender

2023

ACS Med. Chem. Lett.

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Gene expression and cell morphology data are highdimensional biological readouts of much recent interest for drug discovery. They are able to describe biological systems in different states (e.g., healthy and diseased), as well as biological systems before and after compound treatment, and they are hence useful for matching both spaces (e.g., for drug repurposing) as well as for characterizing compounds with respect to efficacy and safety endpoints. This Microperspective describes recent advances in this direction with a focus on applied drug discovery and drug repurposing, as well as outlining what else is needed to advance further, with a particular focus on better understanding the applicability domain of readouts and their relevance for decision making, which is currently often still unclear.

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Prediction and identification of synergistic compound combinations against pancreatic cancer cells

Cited by 3 publications

References 80 publications

Pyrvinium Pamoate Enhances the Anti-cancer Activities of Gemcitabine in Pancreatic Cancer

Pyrvinium Pamoate Enhances the Anti-cancer Activities of Gemcitabine in Pancreatic Cancer

Inhibiting the transcription and replication of Ebola viruses by disrupting the nucleoprotein and VP30 protein interaction with small molecules

Using Transcriptomics and Cell Morphology Data in Drug Discovery: The Long Road to Practice

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