title: Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells.
abstract: Uridine-cytidine kinase 2 is an enzyme that is overexpressed in abnormal cell growth and its implication is considered a hallmark of cancer. Due to the selective expression of UCK2 in cancer cells, a selective inhibition of this key enzyme necessitates the discovery of its potential inhibitors for cancer chemotherapy. The present study was carried out to demonstrate the potentials of natural phytochemicals from the rhizome of Alpinia mutica to inhibit UCK2 useful for colorectal cancer. Here, we employed the used of in vitro to investigate the effectiveness of natural UCK2 inhibitors to cause HT-29 cell death. Extracts, flavokawain B, and alpinetin compound from the rhizome of Alpinia mutica was used in the study. The study demonstrated that the expression of UCK2 mRNA were substantially reduced in treated HT-29 cells. In addition, downregulation in expression of 18S ribosomal RNA was also observed in all treated HT-29 cells. This was confirmed by fluorescence imaging to measure the level of expression of 18S ribosomal RNA in live cell images. The study suggests the possibility of MDM2 protein was downregulated and its suppression subsequently activates the expression of p53 during inhibition of UCK2 enzyme. The expression of p53 is directly linked to a blockage of cell cycle progression at G0/G1 phase and upregulates Bax, cytochrome c, and caspase 3 while Bcl2 was deregulated. In this respect, apoptosis induction and DNA fragmentation were observed in treated HT-29 cells. Initial results from in vitro studies have shown the ability of the bioactive compounds of flavokawain B and alpinetin to target UCK2 enzyme specifically, inducing cell cycle arrest and subsequently leading to cancer cell death, possibly through interfering the MDM2-p53 signalling pathway. These phenomena have proven that the bioactive compounds could be useful for future therapeutic use in colon cancer.
authors.affiliation: Laboratory of MAKNA-Cancer Research, Institute of Bioscience, Universiti Putra Malaysia Serdang, Selangor, Malaysia.|Department of Pharmacognosy and Ethnopharmacy, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
authors.forename: Ibrahim
authors.identifier: http://orcid.org/0000-0001-9271-6927
authors.initials: I
authors.lastname: Malami
authors.affiliation: Laboratory of MAKNA-Cancer Research, Institute of Bioscience, Universiti Putra Malaysia Serdang, Selangor, Malaysia.|Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Ahmad Bustamam
authors.initials: AB
authors.lastname: Abdul
authors.affiliation: Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Rasedee
authors.initials: R
authors.lastname: Abdullah
authors.affiliation: Department of Chemistry, Faculty of Science, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Nur Kartinee Bt
authors.initials: NK
authors.lastname: Kassim
authors.affiliation: Laboratory of MAKNA-Cancer Research, Institute of Bioscience, Universiti Putra Malaysia Serdang, Selangor, Malaysia.|Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: Rozita
authors.initials: R
authors.lastname: Rosli
authors.affiliation: Laboratory of Vaccine and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Swee Keong
authors.initials: SK
authors.lastname: Yeap
authors.affiliation: Laboratory of MAKNA-Cancer Research, Institute of Bioscience, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Peter
authors.initials: P
authors.lastname: Waziri
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Imaobong Christopher
authors.initials: IC
authors.lastname: Etti
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia Serdang, Selangor, Malaysia.
authors.forename: Muhammad Bashir
authors.initials: MB
authors.lastname: Bello
mesh_terms: D032429:Alpinia / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000096:biosynthesis* / Q000235:genetics; D027343:Rhizome / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D014541:Uridine Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D010936:Plant Extracts; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C436748:alpinetin; C452039:flavokawain B; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C483834:UCK2 protein, human; D014541:Uridine Kinase