Charah T. Watson

Cycloartane-3,24,25-triol inhibits MRCKα kinase and demonstrates promising anti prostate cancer activity in vitro

BackgroundGiven the high occurrence of prostate cancer worldwide and one of the major sources of the discovery of new lead molecules being medicinal plants, this research undertook to investigate the possible anti-cancer activity of two natural cycloartanes; cycloartane-3,24,25-diol (extracted in our lab from Tillandsia recurvata) and cycloartane-3,24,25-triol (purchased). The inhibition of MRCKα kinase has emerged as a potential solution to restoring the tight regulation of normal cellular growth, the loss of which leads to cancer cell formation.MethodsKinase inhibition was investigated using competition binding (to the ATP sites) assays which have been previously established and authenticated and cell proliferation was measured using the WST-1 assay.ResultsCycloartane-3,24,25-triol demonstrated strong selectivity towards the MRCKα kinase with a Kd50 of 0.26 μM from a total of 451 kinases investigated. Cycloartane-3,24,25-triol reduced the viability of PC-3 and DU145 cell lines with IC50 values of 2.226 ± 0.28 μM and 1.67 ± 0.18 μM respectively.ConclusionsThese results will prove useful in drug discovery as Cycloartane-3,24,25-triol has shown potential for development as an anti-cancer agent against prostate cancer.

Cycloartanes with Anticancer Activity Demonstrate Promising inhibition of the Mrckα and Mrckβ Kinases

Aim:The role of Kinases in cancer onset and progression has made kinases a target for the control of some cancers.Recent discoveries that kinases are most effectively inhibited bysmall molecules havealso resulted in an increased search for small molecule kinase inhibitors. Cycloartanes are small molecules found in many medicinal plants including the Jamaican Ball Moss ( Tillandsia recurvata ). Recent studies onT. recurvatahave demonstrated that it possesses anticancer activity. Cycloartane -3,24,25- triol, an analog of a cycloartane identified in Ball moss was also shown to have inhibitory activity against MRCK�± kinase. This study was as such set up to determine the MRCK�±/�≤ kinase i nhibition activity of other cycloartanes in Ball Moss and their analogs. MRCK�±/�≤ kinases has been identified as an important kinase implicated in cancer onset and progression and as such a potential drug target. Methodology :Kinase inhibition activity of 6 cycloartanes was investigated using the

Petiveria alliacea L (Guinea Hen Weed) and Its Major Metabolite Dibenzyl Trisulfide Demonstrate HIV-1 Reverse Transcriptase Inhibitory Activity

Aim: The human immunodeficiency virus (HIV) remains a major public health concern despite the discovery and development of Highly Active Antiretroviral Therapies (HAART). There is as such a need to continue to search for new and effective therapies for this global pandemic. In an effort to discover new anti HIV agents, the aim of this study was to determine the anti HIV-1 activity of Petiveria alliacea and its metabolites . Methodology: The extracts of P. alliacea and dibenzyl trisulfide were screened for anti HIV-1 properties in primary peripheral blood mononuclear cells (PBMCs) infected with the HIV-1JR-CSF strain.

Anti HIV-1 Activity of the Crude Extracts of Guaiacum officinale L. (Zygophyllaceae).

Aim: Jamaica is rich in medicinal plants. Guaiacum officinale is the “National Flower”, with reported uses in folk medicine for the treatment of various conditions including inflammation. In our search for plants with anticancer and anti-infective properties, we evaluated Guaiacum officinale for activity against HIV-1. Methodology: The leaf, seed and twig extracts of G. officinale were screened for anti HIV-1 properties in primary peripheral blood mononuclear cells (PBMCs) infected with the reference HIV-1 BaL strain. Results: All the tested extracts inhibited HIV-1 p24 production by infected cells, with EC50 concentrations of 22.35μg/ml, 23.42μg/ml and 25.04μg/ml, respectively for the leaf, seed and twig extracts. As comparison, Betulinic acid had an EC50 value of 27.50μg/ml. The tested extracts had IC50/EC50 selectivity index (SI) values of ≥ 3, which compared favorably to Betulinic acid SI value of 1.09. Conclusion: The results of this study suggest that extracts of G. officinale may provide leads for the discovery of new drug agents against HIV-1. Short Research Article European Journal of Medicinal Plants, 4(4): 483-489, 2014 484

Unearthing the medicinal properties of Tillandsia recurvata (Ball Moss): a mini review.

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Abstract 1754: Cycloartane anticancer activity

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA New cancer diagnoses remain on the rise despite significant improvements in early detection and treatment. The role of Kinases in cancer onset and progression has made kinases a target for the control of some cancers. The MRCKα/β kinases have recently been implicated in cancer onset and progression and as such could serve as a potential drug target. The discovery that kinases are most effectively inhibited by small molecules has also resulted in an increased search for small molecule kinase inhibitors. Cycloartanes are small molecules found in many medicinal plants including the Jamaican Ball Moss (Tillandsia recurvata). Recent studies on T. recurvata have demonstrated that it possesses significant anticancer activity. Cycloartane-3,24,25-triol, an analog of a cycloartane identified in Ball moss was also shown to have inhibitory activity against MRCKα kinase. This study was as such set up to determine the MRCKα/β kinase inhibition activity of other cycloartanes in Ball Moss and their analogs. The kinase inhibitory activity of 6 cycloartanes was investigated using the ligand-kinase binding assay while the WST-1 reagent assay was used to determine the antiproliferative activity of the cycloartanes against some prostate and breast cancer cell lines. Cycloart-23-ene-3,25-diol (1), Cycloartane-3,24,25-triol (2), Cycloart-25-ene-3,24-diol (3), 3,23-Dioxo-9,19-cyclolanost-24-en-26-oic acid (4), 24,25-Dihydroxycycloartan-3-one (5) inhibited the MRCKα kinase with Kd of 0.21 μM, 0.25µM, 0.36 µM, 3.0 µM, and 2.1 µM respectively. Hydroxycycloart-23-en-3-one,25, (6) showed no inhibition against the MRCKα kinase. Compounds 1, 3, 4, 5 inhibited the MRCKβ kinase with Kd of 4.7 μM, 1.10 µM, 3.2 µM, and 9.8 µM, respectively. Three of the six cycloartanes exhibited antiproliferation activity against two prostate and breast cancer cell lines each. In conclusion, cycloart-23-ene-3,25-diol (1) showed the most promising activity against the MRCKα/β kinase out of the 6 cycloartanes screened demonstrating an interesting structure activity relationship profile when compared with the other molecules. Cycloart-23-ene-3,25-diol (1) deserves further studies to determine its in vivo efficacy and safety. Citation Format: Henry Isaac Cloore Lowe, Ngeh J. Toyang, Charah Watson, Joseph Bryant. Cycloartane anticancer activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1754. doi:10.1158/1538-7445.AM2014-1754