ABSTRACT
Crinumasiaticum is a perennial herb widely distributed in many warmer regions, including Thailand, and is well-known for its medicinal and ornamental values. Crinum alkaloids contain numerous compounds, such as crinamine. Even though its mechanism of action is still unknown, crinamine was previously shown to possess anticancer activity. In this study, we demonstrate that crinamine was more cytotoxic to cervical cancer cells than normal cells. It also inhibited anchorage-independent tumor spheroid growth more effectively than existing chemotherapeutic drugs carboplatin and 5-fluorouracil or the CDK9 inhibitor FIT-039. Additionally, unlike cisplatin, crinamine induced apoptosis without promoting DNA double-strand breaks. It suppressed cervical cancer cell migration by inhibiting the expression of positive regulators of epithelial-mesenchymal transition SNAI1 and VIM. Importantly, crinamine also exerted anti-angiogenic activities by inhibiting secretion of VEGF-A protein in cervical cancer cells and blood vessel development in zebrafish embryos. Gene expression analysis revealed that its mechanism of action might be attributed, in part, to downregulation of cancer-related genes, such as AKT1, BCL2L1, CCND1, CDK4, PLK1, and RHOA. Our findings provide a first insight into crinamine's anticancer activity, highlighting its potential use as an alternative bioactive compound for cervical cancer chemoprevention and therapy.
Subject(s)
Amaryllidaceae Alkaloids/administration & dosage , Angiogenesis Inhibitors/administration & dosage , Crinum/chemistry , Snail Family Transcription Factors/metabolism , Uterine Cervical Neoplasms/metabolism , Vimentin/metabolism , Amaryllidaceae Alkaloids/pharmacology , Angiogenesis Inhibitors/pharmacology , Animals , Carboplatin/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Embryo, Nonmammalian/blood supply , Embryo, Nonmammalian/drug effects , Epithelial-Mesenchymal Transition/drug effects , Female , Fluorouracil/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Plant Extracts/chemistry , Pyridines/pharmacology , Uterine Cervical Neoplasms/blood supply , Uterine Cervical Neoplasms/drug therapy , Zebrafish/embryologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Hippadine is an alkaloid isolated from Crinum macowanii. Crinum macowanii is used in South Africa to treat oedema, 'heart disease', rheumatic fever, cancer and skin diseases, and belongs to the plant family Amaryllidaceae, assumed to have originated in the South African region. The aim of this study was to evaluate the effect of hippadine, an alkaloid extracted from Crinum macowanii, on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive Wistar rats (SHR); and to find out if α1 and⧸or ß1 adrenoceptors contribute to its effects. MATERIALS AND METHODS: Hippadine (2.5-12.5mg/kg), adrenaline (0.05-0.20mg/kg), atenolol (0.5-40mg/kg) and prazosin hydrochloride (100-500µg/kg) were infused intravenously, and the BP and HR measured via a pressure transducer connecting the femoral artery and the PowerLab. Adrenaline increased the systolic, diastolic and mean arterial BP, while hippadine, atenolol and prazosin respectively decreased the systolic, diastolic and mean arterial BP. Increases in HR were observed with both adrenaline and prazosin, while reductions in HR were observed with atenolol and hippadine. Infusion of adrenaline in rats pre-treated with atenolol (30mg/kg), prazosin (400µg/kg), and hippadine (10mg/kg) led to similar increases in BP and HR in all groups. All changes in HR or BP were significant (p<0.05) and dose dependent. CONCLUSION: Hippadine decreases the BP and HR in SHR, and these effects may be due to α1 and ß1 adrenoceptor inhibition.
Subject(s)
Amaryllidaceae Alkaloids/pharmacology , Blood Pressure/drug effects , Crinum/chemistry , Heart Rate/drug effects , Amaryllidaceae Alkaloids/administration & dosage , Amaryllidaceae Alkaloids/isolation & purification , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/isolation & purification , Antihypertensive Agents/pharmacology , Atenolol/administration & dosage , Atenolol/pharmacology , Dose-Response Relationship, Drug , Epinephrine/administration & dosage , Epinephrine/pharmacology , Hypertension/drug therapy , Male , Medicine, African Traditional , Prazosin/administration & dosage , Prazosin/pharmacology , Rats , Rats, Inbred SHR , Rats, Wistar , South AfricaABSTRACT
Lycorine, which is the most abundant alkaloid isolated from the Amaryllidaceae family of plants, reportedly exhibits promising anticancer activities. Herein, a series of novel lycorine derivatives were synthesized and evaluated for their in vitro inhibitory activities against seven different cancer cell lines, including A549, HCT116, SK-OV-3, NCI-H460, K562, MCF-7 and HL-60. The results indicated that compounds bearing diverse amine substituents at the C-2 position demonstrated good anticancer activities. The selectivity towards different cancer cell lines of the synthesized derivatives is discussed.