Small-molecule screening of PC3 prostate cancer cells identifies tilorone dihydrochloride to selectively inhibit cell growth based on cyclin-dependent kinase 5 expression

Wissing, Michel D.; Dadon, Tikva; Kim, Eunice; Piontek, Klaus; Shim, Joong Sup; Kaelber, Nadine S.; Liu, Jun O.; Kachhap, Sushant K.; Nelkin, Barry D.

doi:10.3892/or.2014.3174

Cited by 21 publications

(17 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tilorone is an investigational agent that has been known for over 40 years as an antiviral 56 and is an inducer of interferon in mice 57 . It has been shown to possess a broad array of biological activities including cell growth inhibition in PC3 CDK5dn prostate cancer cells (IC 50 8–12 μM) 58 , inhibition of Primase DnaG from Bacillus anthracis (IC 50 7.1 μM) 59 , in a mouse model of pulmonary fibrosis it decreased lung hydroxyproline content and the expression of collagen genes 60 , α7 nicotinic receptor (nAChR) agonist activity (K i 56 nM) 61 , activated human alpha7 nAChR with an EC 50 value of 2.5 μM 62 , radioprotective activity 63 , potent modulation of HIF-mediated gene expression in neurons with neuroprotective properties 64 and induction of the accumulation of glycosaminoglycans, delay infectious prion clearance, and prolong prion disease incubation time 65 . Quinacrine is an old antimalarial drug now more widely used as an antiprotozoal for the treatment of giardiasis 66 and as an anthelmintic.…”

Section: Discussionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

View full text Add to dashboard Cite

The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.

show abstract

Section: Discussionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

View full text Add to dashboard Cite

show abstract

“…CDK5-dependent phosphorylation of the talin head domain at Ser425 prevents its ubiquitylation and degradation, regulating stability of cellular adhesion and cell migration [25]. Recently, CDK5 has been demonstrated to be involved in pancreatic [26], lung, and prostate [27] cancer. Although the in vitro and in vivo expression profiles of CDK5 have been investigated in several types of cancer, no published data on the expression and function of CDK5 in prolactin pituitary adenomas are available except for a report by Xie et al [7].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

Xie

Liu

Wu³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Pituitary adenomas constitute 15-20% of intracranial neoplasms. Previously we reported that cyclin-dependent kinase 5 (CDK5) is upregulated in pituitary tumors associated with activating protein p35, and plays an essential role in pituitary adenomas progression. Here we explored the mechanisms of CDK5 signaling in prolactin pituitary adenomas. Our data indicate that p35 expression and CDK5 activity are both significantly increased in human invasive prolactin pituitary adenomas as compared to noninvasive forms of pituitary adenomas. Inhibition of CDK5 activity suppressed cell migration and invasive ability in GH3 rat pituitary cells. We identified that CDK5 phosphorylates serine 229 residue (Ser-229) of kinase insert domain receptor (KDR), also known as VEGFR-2, in prolactin pituitary adenomas. Phosphorylation of Ser-229 is required for proper KDR surface localization. Phosphorylated Ser-229 in KDR (pSer-229) levels are significantly higher in noninvasive and invasive prolactin pituitary adenomas compared to normal pituitary tissues. In addition, our data indicated that higher KDR pSer-229 correlates with worse prognosis in patients with prolactin pituitary adenomas. In summary, our results illustrated that CDK5-mediated KDR phosphorylation controls prolactin pituitary adenoma progression and KDR pSer-229 serves as a potential prognostic biomarker for both noninvasive and invasive pituitary adenomas.

show abstract

“…Co-treatment of roscovitine and irrinotecan arrests HCC growth in mouse models [34]. Combining Cdk5 inhibition with the antiviral agent, tilorone, selectively inhibited growth, proliferation and invasive phenotype of prostate cancer cells [59], while using the Cdk5 inhibitor AC1MMYR2 in combination with the chemotherapy agent, Paclitaxel may prevent resistance associated with the use of Paclitaxel [60, 61]. …”

Section: Current Strategies For Cdk5 Targetingmentioning

confidence: 99%

The Emerging Role of Cdk5 in Cancer

2016

View full text Add to dashboard Cite

Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies. We subsequently discuss existing and new strategies for targeting Cdk5 and its downstream mechanisms as anti-cancer treatments.

show abstract

Small-molecule screening of PC3 prostate cancer cells identifies tilorone dihydrochloride to selectively inhibit cell growth based on cyclin-dependent kinase 5 expression

Cited by 21 publications

References 33 publications

Machine learning models identify molecules active against the Ebola virus in vitro

Machine learning models identify molecules active against the Ebola virus in vitro

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

The Emerging Role of Cdk5 in Cancer

Contact Info

Product

Resources

About