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Fulltext Anticancer activity of Momordica cochinchinensis (red gac) aril and the impact of varietal diversity

Wimalasiri D, Dekiwadia C, Fong SY, Piva TJ, Huynh T

BMC Complement Med Ther, 2020 Nov 25;20(1):365.
PMID: 33238969 DOI: 10.1186/s12906-020-03122-z

BACKGROUND: Momordica cochinchinensis (Cucurbitaceae) is a nutritionally and medicinally important fruit restricted to South East Asia with diverse morphological and genetic variations but there is limited information on its medicinal potential.
METHODS: M. cochinchinensis aril from 44 different samples in Australia, Thailand and Vietnam were extracted using different solvents and tested for its anticancer potential. Anticancer activity of M. cochinchinensis aril on breast cancer (MCF7 and BT474) and melanoma (MM418C1 and D24) cells were compared to control fibroblasts (NHDF). The cytotoxicity of the cells following treatment with the aril extract was determined using CCK-8 assay. Biochemical and morphological changes were analysed using flow cytometry, confocal and transmission electron microscopy to determine the mechanism of cell death.
RESULTS: The water extract from the aril of M. cochinchinensis elicited significantly higher cytotoxicity towards breast cancer and melanoma cells than the HAE extract. The IC50 concentration for the crude water extract ranged from 0.49 to 0.73 mg/mL and induced both apoptotic and necrotic cell death in a dose- and time-dependant manner with typical biochemical and morphological characteristics. The greatest cytotoxicity was observed from Northern Vietnam samples which caused 70 and 50% melanoma and breast cancer cell death, respectively.
CONCLUSIONS: The water extract of M. cochinchinensis aril caused significant apoptosis and necrosis of breast cancer and melanoma cells, with varieties from Northern Vietnam possessing superior activity. This highlights the potential of this fruit in the development of novel anticancer agents against such tumours, with specific regions on where to collect the best variety and extraction solvent for optimum activity.
Peptidyl-prolyl isomerases: functionality and potential therapeutic targets in cardiovascular disease

Rostam MA, Piva TJ, Rezaei HB, Kamato D, Little PJ, Zheng W, et al.

Clin Exp Pharmacol Physiol, 2015 Feb;42(2):117-24.
PMID: 25377120 DOI: 10.1111/1440-1681.12335

Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.
The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle

Rostam MA, Kamato D, Piva TJ, Zheng W, Little PJ, Osman N

Cell Signal, 2016 08;28(8):956-66.
PMID: 27153775 DOI: 10.1016/j.cellsig.2016.05.002

Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF-β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzyme in chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.
Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam MA, Shajimoon A, Kamato D, Mitra P, Piva TJ, Getachew R, et al.

J. Pharmacol. Exp. Ther., 2018 04;365(1):156-164.
PMID: 29438988 DOI: 10.1124/jpet.117.244483

Transforming growth factor-β (TGF-β) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-β-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-β-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-β-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-β-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-β, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.