Association of cytochromes P450 3A4*22 and 3A5*3 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients.

BACKGROUNDS: Inter-individual variability in response to statin was mainly due to genetic differences. This study aimed to investigate the association of CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746) single nucleotide polymorphism (SNP) with response to simvastatin in hypercholesterolemia patients conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia. PATIENTS AND METHODS: A total of 274 participants were registered in the current study. Hypercholesterolemic patients taking simvastatin 20 mg (n = 148) and control subjects (n = 126) were tested for rs35599367 and rs776746 genotypes using Custom Taqman ® Assay Probes. Response to simvastatin in these patients was assessed by determination of low density lipoprotein (LDL-C), total cholesterol (TC) and by measuring statin plasma levels using Liquid Chromatography-Mass Spectrometry (LC-MS). RESULTS: None of the participants carried a homozygous CYP3A4*22 mutant genotype, while 12 (4.4%) individuals had a heterozygous genotype and 262 (95.6%) had a wild homozygous genotype. The CYP3A5*3 allele was detected in the homozygous mutant form in 16 (5.8%) individuals, while 74 (27.0%) individuals carried the heterozygous genotype and 184 (67.2%) carried the wildtype homozygous genotype. Of the patient group, 15 (11%) were classified as intermediate metabolizers (IMs) and 133 (89%) as extensive metabolizers (EMs). Plasma simvastatin concentrations for the combined CYP3A4/5 genotypes were significantly (P<0.05) higher in the IMs group than in the EMs group. TC and plasma LDL-C levels were also significantly (P<0.05) higher in IMs than in EMs. CONCLUSION: The present study showed associations between CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) SNP combination genotypes with response to statins in hypercholesterolemia. Patients who had either a mutant homozygous allele for CYP3A5*3 or mutant homozygous and heterozygous alleles for CYP3A4*22 showed increased response to lower TC and LDL-C levels.

Molecular designing, virtual screening and docking study of novel curcumin analogue as mutation (S769L and K846R) selective inhibitor for EGFR.

The somatic mutations in ATP binding cleft of the tyrosine kinase binding domain of EGFR are known to occur in 15-40% of non-small cell lung cancer (NSCLC) patients. Although first and second generation anti-EGFR inhibitors are widely used to treat these patients, their therapeutic efficacy is modest and often results in adverse effects or drug resistance. Therefore, there is a need to develop novel as well as safe anti-EGFR drugs. The rapid emergence of computational drug designing provided a great opportunity to both discover and predict the efficacy of novel EGFR inhibitors from plant sources. In the present study, we designed several chemical analogues of edible curcumin (CUCM) compound and assessed their drug likeliness, ADME and toxicity properties using a diverse range of advanced computational methods. We also have examined the structural plasticity and binding characteristics of EGFR wild-type and mutant forms (S769L and K846R) against ligand molecules like Gefitinib, native CUCM, and different CUCM analogues. Through multidimensional experimental approaches, we conclude that CUCM-36 ((1E,4Z,6E)-1-(3,4-Diphenoxyphenyl)-5-hydroxy-7-(4-hydroxy-3-phenoxyphenyl)-1,4,6-heptatrien-3-one) is the best anti-EGFR compound with high drug-likeness, ADME properties, and low toxicity properties. CUCM-36 compound has demonstrated better affinity towards both wild-type (ΔG is -8.5 kcal/Mol) and mutant forms (V769L & K846R; ΔG for both is >-9.20 kcal/Mol) compared to natural CUCM and Gefitinib inhibitor. This study advises the future laboratory assays to develop CUCM-36 as a novel drug compound for treating EGFR positive non-small cell lung cancer patients.

Correction to: Chemosensitizing and nephroprotective effect of resveratrol in cisplatin-treated animals.

[This corrects the article DOI: 10.1186/s12935-014-0152-2.].

Chemosensitizing and nephroprotective effect of resveratrol in cisplatin -treated animals.

BACKGROUND: Cisplatin (CIS) is one of the most effective anticancer drug used in the treatment of several solid tumors .Its use is limited by its nephrotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of CIS and the possible protective effect against CIS-induced nephrotoxicity in rats. METHODS: The percent survival of female tumor bearing mice was used for determination the cytotoxic activity of CIS in the presence or the absence of RSVL. Uptake and cell cycle effect, serum creatinine (CREA), blood urea nitrogen (BUN), Reduced Glutathione (GSH) and histopatholgical examination of kidney tissues after CIS and/or RSVL therapy were also investigated. RESULTS: RSVL increased the intracellular level of CIS in EAC cells and there was a strong correlation between the high cellular level of CIS and its cytotoxicity. CIS at a dose level of 5 mg/kg increased the mean survival time of female tumor bearing mice to 25 days compared with 17 days for tumor-bearing control mice. Administration of RSVL at a dose level of 25 mg/kg simultaneously with CIS increased the mean survival time to 48 days with 60% survival of the tumor-bearing animals. Cell cycle analysis of tumor cells showed that CIS treatment decreases the proliferation index of tumor cells while in presence of RSVL there was more significant inhibitions. Also, CIS treatment caused increase in level of creatinine and blood urea with significant decrease in the GSH level. While, in the presence of RSVL, level of creatinine and blood urea restored to control level. CONCLUSION: This study suggests that RSVL could increase the cytotoxic activity of CIS and protect against its nephrotoxicity.

Amelioration of doxorubicin­induced cardiotoxicity by resveratrol.

Doxorubicin (DOX), is a highly active anticancer agent, but its clinical use is limited by its severe cardiotoxic side­effects associated with increased oxidative stress and apoptosis. Resveratrol (RSVL) is a naturally occurring polyphenolic compound (trans-3,5,4'-trihydroxystilbene) found primarily in root extracts of the oriental plant Polygonum cuspidatum and of numerous additional plant species. It has recently been shown that RSVL has a number of beneficial effects in different biological systems, which include anti-oxidant, antineoplastic, anticarcinogenic, cardioprotective and antiviral effects. In this study, we examined whether RSVL has protective effects against DOX­induced free radical production and cardiotoxicity in male rats. The tested dose of DOX (20 mg/kg) caused a significant increase in the serum activities of the cardiac enzymes lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) and the level of malondialdehyde (MDA) in the heart tissue. However, there was a significant decrease in the glutathione level in the heart tissue. Simultaneous treatment of rats with RSVL [10 mg/kg, intraperitoneal (i.p.) injection] reduced the activity of LDH and CPK and significantly reduced MDA production in the heart. The total antioxidant capacity was increased following RSVL administration. Electron microscopy examination of the heart tissue showed that DOX treatment results in massive fragmentation and lysis of the myofibrils, and that mitochondria show either vacuolization or complete loss of the cristae. Simultaneous treatment with RSVL ameliorated the effect of DOX administration on cardiac tissue, with cardiomyocytes appearing normal compared to the control samples, and mitochondria retaining their normal structure.

Chemosensetizing and cardioprotective effects of resveratrol in doxorubicin- treated animals.

BACKGROUND: Doxorubicin (DOX), an anthracycline antibiotic is one of the most effective anticancer drug used in the treatment of variety of cancers .Its use is limited by its cardiotoxicity. The present study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of mammary carcinoma (Ehrlich ascites carcinoma) to the action of DOX and at the same time its protective effect against DOX-induced cardiotoxicity in rats. METHODS: Ehrlich ascites carcinoma bearing mice were used in this study. Percent survival of tumor bearing mice was used for determination of the Cytotoxic activity of DOX in presence and absence of RSVL. Uptake and cell cycle effect of DOX in tumor cells in the presence of RSVL was also determined. Histopatholgical examination of heart tissues after DOX and/or RSVL therapy was also investigated. RESULTS: DOX at a dose level of 15 mg/kg increased the mean survival time of tumor bearing mice to 21 days compared with 15 days for non tumor-bearing control mice. Administration of RSVL at a dose level of 10 mg/kg simultaneously with DOX increased the mean survival time to 30 days with 70% survival of the tumor-bearing animals. RSVL increased the intracellular level of DOX and there was a strong correlation between the high cellular level of DOX and its cytotoxic activity. Moreover, RSVL treatment showed 4.8 fold inhibition in proliferation index of cells treated with DOX. Histopathological analysis of rat heart tissue after a single dose of DOX (20 mg/kg) showed myocytolysis with congestion of blood vessels, cytoplasmic vacuolization and fragmentation. Concomitant treatment with RSVL, fragmentation of the muscle fiber revealed normal muscle fiber. CONCLUSION: This study suggests that RSVL could increase the cytotoxic activity of DOX and at the same time protect against its cardiotoxicity.