Chemopreventive activity of methanol extract of Melastoma malabathricum leaves in DMBA-induced mouse skin carcinogenesis

Background: Melastoma malabathricum L. Smith (family Melastomaceae) is a shrub that has been used by the Malay practitioners of traditional medicine to treat various types of ailments. The present study aimed to determine the chemopreventive activity of methanol extract of M. malabathricum leaves (MEMM) using the standard 7,12-dimethylbenz(α)anthracene (DMBA)/croton oil-induced mouse skin carcinogenesis model. Materials and Methods: In the initiation phase, the mice received a single dose of 100µl/100 µg DMBA (group I-V) or 100µl acetone (group VI) topically on the dorsal shaved skin area followed by the promotion phase involving treatment with the respective test solutions (100 μl of acetone, 10 mg/kg curcumin or MEMM (30, 100 and 300mg/kg)) for 30 min followed by the topical application of tumour promoter (100µl croton oil). Tumors were examined weekly and the experiment lasted for 15 weeks. Results: MEMM and curcumin significantly (p<0.05) reduced the tumour burden, tumour incidence and tumour volume, which were further supported by the histopathological findings. Conclusion: MEMM demonstrated chemoprevention possibly via its antioxidant and anti-inflammatory activities, and the action of flavonoids like quercitrin

A bismuth diethyldithiocarbamate compound promotes apoptosis in HepG2 carcinoma, cell cycle arrest and inhibits cell invasion through modulation of the NF-κB activation pathway

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

G2/M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph3PAu[SC(OR) = NPh], R = Me, Et, and iPr, during zebrafish development

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 24 h; 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 7.64 μM for 1–3). Finally, the zebrafish tolerated doses of 1 and 2 up to 0.625 μM, and 3 was tolerated at even higher doses of up to 1.25 μM

CHEMOPREVENTIVE ACTIVITY OF METHANOL EXTRACT OF MELASTOMA MALABATHRICUM LEAVES IN DMBA-INDUCED MOUSE SKIN CARCINOGENESIS

Background: Melastoma malabathricum L. Smith (family Melastomaceae) is a shrub that has been used by the Malay practitioners of traditional medicine to treat various types of ailments. The present study aimed to determine the chemopreventive activity of methanol extract of M. malabathricum leaves (MEMM) using the standard 7,12-dimethylbenz(α)anthracene (DMBA)/croton oil-induced mouse skin carcinogenesis model. Materials and Methods: In the initiation phase, the mice received a single dose of 100µl/100 µg DMBA (group I-V) or 100µl acetone (group VI) topically on the dorsal shaved skin area followed by the promotion phase involving treatment with the respective test solutions (100 μl of acetone, 10 mg/kg curcumin or MEMM (30, 100 and 300mg/kg)) for 30 min followed by the topical application of tumour promoter (100µl croton oil). Tumors were examined weekly and the experiment lasted for 15 weeks. Results: MEMM and curcumin significantly (

Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents

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

The influence of R substituents in triphenylphosphinegold(I) carbonimidothioates, Ph 3PAu[SC(OR) = NPh] (R = Me, Et and iPr), upon in vitro cytotoxicity against the HT-29 colon cancer cell line and upon apoptotic pathways

The Ph3PAu[SC(OR) = NPh], R = Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with1 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. Compound1 activates the p73 gene, whereas each of2 and3 activates the p53 gene. An additional apoptotic mechanism is exhibited by2, that is, via the JNK/MAP pathway

Apoptosis and cell cycle arrest of MCF-7R breast carcinoma cells by bis(phosphane)copper(I) thiocarbamides derivative compounds

Previous studies on coordinated gold compounds namely phosphanegold(I) thiocarbamides exhibited promising anti-cancer activities through induction of apoptosis. To a greater extent, current research was advanced to study copper(I) derivatives, namely bis(phosphane)copper(I) thiocarbamides, (Ph3P)2Cu[S=C(OR)N(H)Ph]Cl, with R referring as three different substituent group: methyl (Compound1), ethyl (Compound2), and isopropyl (Compound3); on breast cancer. Among the aggressive cancers reported, breast cancer exhibited poor response to chemotherapy owing to its high cellular glutathione (GSH) levels, high mitochondrial thioredoxin reductase (TrxR) activities and over-activation of NF-κB; hence, contributed for reduced drug’s efficacy and resistance to death-signals. Thus, regulation on GSH, TrxR and NF-κB are suitable targets in current study. The tested copper(I) compounds demonstrated in-vitrocytotoxicity against MCF-7R breast carcinoma cells with micromolar potency. Meanwhile, cytotoxicity testing on normal cells (kidney, breast and heart) suggest Compound1–3are less potent towards normal cells and selective towards breast cancer cells. Inhibition of TrxR yield increase of cellular level of reactive oxygen species and further mitochondria membrane polarization, indicating Compound 1–3 inhibit mitochondrial functionvia oxidative stress. The detailed mechanistic studies demonstratedCompound 1–3 inducedboth intrinsic and extrinsic pathway of apoptosis through upregulation of p53/p73 genes and interaction with cell-death receptor. Also, Compound 1–3arrest the cell cycle of MCF-7R cells through activation of S-phase cell cycle checkpoint via modulation of cyclins and cyclin-dependent kinases. The NF-κB pathway is also down-regulated by Compound 1–3through the regulation of Lys48-and Lys63-linked polyubiquitination. From the summary of apoptosis and cell cycle pathway, it can be concluded different mechanisms are mediated by differing the nature of substituent groups in compounds hence they possess potential as anti-cancer agents

Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

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

Barriers to smoking cessation: a qualitative study from the perspective of primary care in Malaysia

Objectives: This qualitative study aims to construct a model of the barriers to smoking cessation in the primary care setting. Design: Individual in-depth, semistructured interviews were audio-taped, then verbatim transcribed and translated when necessary. The data were first independently coded and then collectively discussed for emergent themes using the Straussian grounded theory method. Participants and setting: Fifty-seven current smokers were recruited from a previous smoking related study carried out in a primary care setting in Malaysia. Current smokers with at least one failed quit attempts were included. Results: A five-theme model emerged from this grounded theory method. (1) Personal and lifestyle factors: participants were unable to resist the temptation to smoke; (2) Nicotine addiction: withdrawal symptoms could not be overcome; (3) Social cultural norms: participants identified accepting cigarettes from friends as a token of friendship to be problematic; (4) Misconception: perception among smokers that ability to quit was solely based on one's ability to achieve mind control, and perception that stopping smoking will harm the body and (5) Failed assisted smoking cessation: smoking cessation services were not felt to be user-friendly and were poorly understood. The themes were organised into five concentric circles based on time frame: those actionable in the short term (themes 1 and 2) and the long term (themes 3, 4, 5). Conclusions: Five themes of specific beliefs and practices prevented smokers from quitting. Clinicians need to work on these barriers, which can be guided by the recommended time frames to help patients to succeed in smoking cessation.</p