RESUMEN
This work aimed to evaluate the effects of encapsulated tocotrienols (TRF) and caffeic acid (CA) in water-in-oil-in-water (W/O/W) multiple nanoemulsion with cisplatin towards cancer cells. This work is important considering the limited efficacy of cisplatin due to tumour resistance, as well as its severe side effects. A549 and HEP G2 cancer cell lines were utilised for evaluating the efficacy of the encapsulated W/O/W while HEK 293 normal cell line was used for evaluating the toxicity. TRF, CA and CIS synergistically improved apoptosis in the late apoptotic phase in A549 and HEP G2 by 23.1% and 24.9%, respectively. The generation of ROS was enhanced using TRF:CA:CIS by 16.9% and 30.2% for A549 and HEP G2, respectively. Cell cycle analysis showed an enhanced cell arrest in the G0/G1 phase for both A549 and HEP G2. TRF, CA and CIS led to cell death in A549 and HEP G2. For HEK 293, ~33% cell viability was found when only CIS was used while >95% cell viability was observed when TRF, CA and CIS were used. This study demonstrates that the encapsulated TRF and CA in W/O/W with CIS synergistically improved therapeutic efficacy towards cancer cells, as well as lowered the toxicity effects towards normal cells.
Asunto(s)
Antineoplásicos , Neoplasias , Tocotrienoles , Antineoplásicos/farmacología , Apoptosis , Ácidos Cafeicos , Línea Celular Tumoral , Cisplatino/farmacología , Células HEK293 , Humanos , Tocotrienoles/farmacologíaRESUMEN
Early development of liver cancer is usually asymptomatic. The overall survival rate of patients is relatively low due to late diagnosis, despite hepatocellular carcinoma being a common diagnosis. The high mortality rate of liver cancer was due to its overactivated cellular mitochondrial activities, namely thioredoxin reductase enzymatic activities and its downstream activation of nuclear factor kappa B (NF-κB) signaling pathways for cancer cell migration. Our previous study on this candidate compound on A2780 ovarian cancer cells and MCF-7 breast cancer cells, through modulation of cell-cycle checkpoints and respective targeted apoptosis pathways. The current study used HepG2 hepatocellular carcinoma cell lines as a representative in vitro liver cancer cell model. The half maximal inhibitory concentration (IC50) value was obtained via incubation of PTZ compound for 24 h yield of 37.03 µM, whereby it was three-fold more potent than the standard control tested, cisplatin (109.23 µM). The subsequent application of IC50 dosage of PTZ onto HepG2 cells illustrated a growth-static effect via activation of S-phase cell-cycle checkpoints, immediately followed by regulation of apoptosis. Increased cellular concentration of reactive oxygen species eventually generated oxidative damages on mitochondria, hence resulting in the release of cytochrome c protein and suppression of TrxR enzymatic activity, in conjunction with the suppression on invasion of cancer cells via Matrigel invasion chamber. In conclusion, PTZ was hypothesized to act effectively on mitochondria of HepG2 cells; hence it should proceed into detailed drug targeting mechanism research.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Mitocondrias/efectos de los fármacos , Fenotiazinas/toxicidad , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologíaRESUMEN
A new era of metal-based drugs started in the 1960s, heralded by the discovery of potent platinum-based complexes, commencing with cisplatin [(H3N)2PtCl2], which are effective anti-cancer chemotherapeutic drugs. While clinical applications of gold-based drugs largely relate to the treatment of rheumatoid arthritis, attention has turned to the investigation of the efficacy of gold(I) and gold(III) compounds for anti-cancer applications. This review article provides an account of the latest research conducted during the last decade or so on the development of gold compounds and their potential activities against several cancers as well as a summary of possible mechanisms of action/biological targets. The promising activities and increasing knowledge of gold-based drug metabolism ensures that continued efforts will be made to develop gold-based anti-cancer agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Oro/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , HumanosRESUMEN
The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (ΔΨm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Fenotiazinas/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HEK293 , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Concentración 50 Inhibidora , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , FN-kappa B/metabolismo , Invasividad Neoplásica , Fenotiazinas/administración & dosificación , Fenotiazinas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), were previously shown to be significantly cytotoxic toward HT-29 cancer cells and to induce cell death by both intrinsic and extrinsic apoptotic pathways whereby 1 activated the p73 gene, and each of 2 and 3 activated p53; 2 also caused apoptotic cell death via the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Apoptosis pathways have been further evaluated by mitochondrial cytochrome c measurements and annexin V screening, confirming apoptotic pathways of cell death. Cell cycle analysis showed the majority of treated HT-29 cells were arrested at the G2/M checkpoint after 24h; results of both assays were confirmed by changes in populations of relevant genes (PCR array analysis). Cell invasion studies showed inhibition of metastasis through Matrigel™ matrix to 17-22% cf. untreated cells. LC50 values were determined in zebrafish (8.36, 8.17, and 7.64µM for 1-3). Finally, the zebrafish tolerated doses of 1 and 2 up to 0.625µM, and 3 was tolerated at even higher doses of up to 1.25µM.
Asunto(s)
Citotoxinas , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Compuestos Orgánicos de Oro , Pez Cebra/embriología , Animales , Línea Celular Tumoral , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Invasividad Neoplásica , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Compuestos Orgánicos de Oro/farmacologíaRESUMEN
In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Tiocarbamatos/farmacología , Inhibidores de Topoisomerasa I/farmacología , Zinc/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Genes p53 , Humanos , FN-kappa B/genética , Invasividad Neoplásica , ARN Mensajero/genética , Ratas , Tiocarbamatos/síntesis química , Tiocarbamatos/química , Tiocarbamatos/toxicidad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/toxicidadRESUMEN
The phosphanegold(I) carbonimidothioates, Ph3PAu{SC(OR)=NC6H4Me-4} for R = Me (1), Et (2) and iPr (3), feature linear P-Au-S coordination geometries and exhibit potent in vitro cytotoxicity against HT-29 colon cancer cells in both monolayer and multi-cellular spheroid models (e.g., IC50 = 11.9 ± 0.4 and 20.3 ± 0.3 µM for 2, respectively). Both intrinsic and extrinsic pathways of apoptosis are demonstrated by human apoptosis PCR array analysis, caspase activities, DNA fragmentation and cell apoptotic assays. Compounds 1-3 induce an extrinsic pathway that leads to down-regulation of NFκB. Compound 2 also exhibits an extrinsic apoptotic pathway involving the activation of both p53 and p73, whereas 3 activates p53 only. Lys48- and Lys63-linked polyubiquitination are also promoted by 1-3. Each of cytotoxic Ph3PAu{SC(OR)=NC6H4Me-4}, for R = Me (1), Et (2) and iPr (3), induce an intrinsic apoptotic pathway as well as an extrinsic pathway leading to down-regulation of NFκB. Lys48- and Lys63-linked polyubiquitination are promoted by 1-3 and these are able to inhibit cell invasion and to suppress the activity of TrxR.
Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , FN-kappa B/metabolismo , Compuestos Orgánicos de Oro/farmacología , Fosfinas/farmacología , Compuestos de Sulfhidrilo/farmacología , Ubiquitinación/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células HT29 , Humanos , Estructura Molecular , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Fosfinas/química , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/químicaRESUMEN
The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.
Asunto(s)
Antineoplásicos/farmacología , Bismuto/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , FN-kappa B/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Apoptosis/genética , Permeabilidad de la Membrana Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteínas Quinasas Asociadas a Muerte Celular/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
A cationic Schiff base ligand, TSB (L) and its Zn (II) complex (1) were synthesized and characterized by using CHN, (1)H-NMR, FT-IR, UV, LC-MS, and X-ray methods. Their ability to inhibit topoisomerase I, DNA cleavage activities, and cytotoxicity were studied. X-ray diffraction study shows that the mononuclear complex 1 is four coordinated with distorted tetrahedral geometry. The singly deprotonated Schiff base ligand L acts as a bidentate ON-donor ligand. Complexation of L increases the inhibitory strength on topoisomerase I activity. Complex 1 could fully inhibit topoisomerase I activity at 250 µM, while L did not show any inhibitory effect on topoisomerase I activity. In addition, L and complex 1 could cleave pBR322 DNA in a concentration and time dependent profile. Surprisingly, L has better DNA cleavage activity than complex 1. The cleavage of DNA by complex 1 is altered in the presence of hydrogen peroxide. Furthermore, L and complex 1 are mildly cytotoxic towards human ovarian cancer A2780 and hepatocellular carcinoma HepG2.
Asunto(s)
Bases de Schiff/síntesis química , Bases de Schiff/farmacología , Zinc/farmacología , Cationes , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , ADN-Topoisomerasas de Tipo I/metabolismo , Electrones , Electroforesis en Gel de Agar , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Bases de Schiff/química , Bases de Schiff/toxicidad , Espectrofotometría Infrarroja , Inhibidores de Topoisomerasa/farmacología , Zinc/toxicidadRESUMEN
The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.