Metachronous Gastrointestinal Stromal Tumors of Different Histologies: An Unusual Case.

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors accounting for only a small fraction of all primary malignant tumors of the gastrointestinal tract. Histologically, GISTs are classified as epithelioid, spindle type, or mixed. We present a case of a 66-year-old male incidentally noted to have a pedunculated gastric mass along the lesser curvature of the stomach during a laparoscopic Nissen fundoplication and hiatal hernia repair. A wedge resection was performed and the pathology demonstrated a 3.7 cm GIST of epithelioid type. Four years after the initial surgery, a jejunal mass was identified via CT enterography as part of a workup for ongoing iron deficiency anemia. A laparoscopic small bowel resection was performed, and the pathology revealed a new primary 3.2 cm GIST of the spindle cell subtype. Three years after surgery, surveillance imaging is negative for any recurrence. This appears to be the first report of the occurrence of metachronous primary GISTs of different histologic subtypes, separated by location.

Hordeum vulgare L. microgreen mitigates reproductive dysfunction and oxidative stress in streptozotocin-induced diabetes and aflatoxicosis in male rats.

Diabetes mellitus type 2 (DM) is a common chronic disease worldwide, which may be due to increased environmental pollution. Aflatoxin B1 is a likely inevitable contaminant in food and dairy products. Both DM and aflatoxicosis exert a deleterious effect on reproduction urging the exploration of various functional food for protection. This study investigated the effect of barley microgreen (BM) on reproductive disorders caused by DM with or without aflatoxicosis in male rats. Rats were divided into eight groups; G1 control, G2 barley, G3 aflatoxin, G4 aflatoxin-barley, G5 streptozotocin (STZ), G6 STZ-barley, G7 STZ-aflatoxin, and G8 STZ-aflatoxin-barley. BM chemical composition revealed elevated calcium, iron, phosphorus, and vitamin A compared with barely seeds. Complete blood picture, lipid profile, serum oxidative stress parameters, relative testicular weight, sperm analysis, chromosomal aberration, and testis histopathology were performed. The lipid profile was altered significantly in G7. Oxidative stress was increased in G3, G5, and G7, whereas it was decreased in BM-treated groups. Sperm counts were reduced significantly in aflatoxin and/or STZ groups but increased significantly in BM-treated groups. Sperm morphological abnormalities and chromosomal aberrations were decreased significantly in BM-treated groups compared with untreated groups. Testicular histopathology revealed moderate diffuse degeneration of seminiferous tubules in aflatoxin and/or STZ groups, which were alleviated in BM-treated groups. In conclusion, aflatoxin and STZ together caused severe reproductive disorder and oxidative stress more than aflatoxin or STZ alone. BM diet reduced significantly oxidative stress and reproductive disorder associated with DM and aflatoxicosis in rats.

Astaxanthin extenuates the inhibition of aldehyde dehydrogenase and Klotho protein expression in cyclophosphamide-induced acute cardiomyopathic rat model.

This study evaluated the mechanistic sequel of aldehyde dehyrogenase (ALDH2) and Klotho protein in cyclophosphamide (CP)-induced cardiotoxicity in rats and the protective effect of astaxanthin (AST) against that sequel. A total of 40 male Wistar albino rats were divided into four groups of 10 animals each: Group 1 was injected intraperitoneally (i.p.) with normal saline for 10 successive days. Group 2 was injected with normal saline for 5 days before and after a single dose of CP (200 mg/kg, i.p.). Group 3 received AST (50 mg/kg/day, i.p.) for 10 days. Group 4 received CP as group 2 and AST as group 3. After the last dose of the treatment protocol, serum was separated to measure cardiotoxicity indices and the left ventricle was then dissected for mRNA and protein expression studies and histopathological examinations. Treatment with CP significantly increased serum lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), and troponin, while significantly decreased soluble α Klotho protein and caused histopathological lesions in cardiac tissues. In cardiac tissues, CP significantly decreased gene expression of ALDH2, Klotho protein, mTOR, IGF, AKT, AMPK, BCL2, but significantly increased expression of BAX and caspase-8. Interestingly, administration of AST in combination with CP completely reversed all the biochemical, histopathological and gene expression changes induced by CP to the control values. The current study suggests that inhibition of ALDH2, Klotho protein, mTOR, and AMPK signals in cardiac tissues may contribute to CP-induced acute cardiomyopathy. AST supplementation attenuates CP-induced cardiotoxicity by modulating ALDH2 and Klotho protein expression in heart tissues, along with its downstream apoptosis effector markers.

Epigenetic immunomodulatory effect of eugenol and astaxanthin on doxorubicin cytotoxicity in hormonal positive breast Cancer cells.

BACKGROUND: Hormonal receptor positive (HR+) breast cancer is the most commonly diagnosed molecular subtype of breast cancer; which showed good response to doxorubicin (DOX)-based chemotherapy. Eugenol (EUG) and astaxanthin (AST) are natural compounds with proved epigenetic and immunomodulatory effects in several cancer cell lines. This study has been initiated to investigate the molecular mechanism (s) whereby EUG and AST could enhance DOX cytotoxicity in MCF7 cells. METHODS: Cytotoxic activity of DOX alone and combined with either 1 mM EUG or 40 µM AST was performed using sulphorhodamine-B assay in MCF7 cells. Global histones acetylation and some immunological markers were investigated using ELISA, western blotting and quantitative RT-PCR techniques. Functional assay of multidrug resistance was performed using rhodamine 123 and Hoechst 3342 dyes. Flow cytometry with annexin V and propidium iodide were used to assess the change in cell cycle and apoptosis along with the expression of some differentiation, apoptosis and autophagy proteins. RESULTS: DOX alone resulted in concentration-dependent cytotoxicity with IC50 of 0.5 µM. Both EUG and AST significantly increased DOX cytotoxicity which is manifested as a significant decrease in DOX IC50 from 0.5 µM to 0.088 µM with EUG and to 0.06 µM with AST. Combinations of DOX with 1 mM EUG or 40 µM AST significantly increased the level of histones acetylation and histone acetyl transferase expression, while reduced the expression of aromatase and epidermal growth factor receptor (EGFR) when compared with 0.25 µM DOX alone. Also both combinations showed higher uptake of rhodamine but lower of Hoechst stains, along with increased the percentage of caspase 3, and decreased the expression of CK7 and LC3BI/II ratio. EUG combination induced IFγ but reduced TNFα causing shifting of cells from G2/M to S and G0/ G1 phases. Combination of DOX with EUG induced apoptosis through the higher BAX/ BCl2 ratio, while with AST was through the increase in caspase 8 expressions. CONCLUSION: EUG and AST potentiated the anticancer activity of DOX through epigenetic histones acetylation along with the immunonomodulation of different apoptotic approaches in MCF7 cells.

Fourier convolution versus derivative spectrophotometry: Application to the analysis of two binary mixtures containing tamsulosin hydrochloride as a minor component.

Simple and rapid spectrophotometric methods are described for determination of two mixtures of tamsulosin (TM), as minor component, with either solifenacin (SL) or tolterodine (TL). The proposed methods involve treatment of the absorbance ratio spectra or zero order spectra by derivative or discrete Fourier function. TM and TL mixture could not be resolved by manipulation of their zero order spectra due to the strong overlap between both spectra and only derivative or Fourier function coefficients of ratio spectra could resolve their spectra. TM and SL mixture was fully resolved by the manipulation of both ratio and zero order spectra. The values of the derivative or the Fourier function coefficients of ratio spectra and/or zero order spectra, at either peak or trough points, were correlated to the concentration of each drug in each mixture. Calibration graphs were linear in ranges 2.5-40 and 30-500µg.mL-1 using derivative ratio and Fourier function ratio, 5-40 and 80-600µg.mL-1 using direct derivative and 2.5-40 and 30-300µg.mL-1 using direct Fourier function for TM and SL, respectively. The plots of derivative ratio amplitude and the Fourier function ratio coefficient versus concentration were linear over ranges 2.5-20 and 25-250µg.mL-1 for TM and TL, respectively. Higher sensitivity as indicated by lower values of detection and quantitation limits were obtained using Fourier convoluted spectra (ratio or zero order) compared to derivative methods. All validation aspects per ICH guidelines are included. The proposed methods were also applied for the studied drugs assay in their tablets and capsules.

Major obstacles to doxorubicin therapy: Cardiotoxicity and drug resistance.

BACKGROUND: Doxorubicin is one of the most commonly prescribed and time-tested anticancer drugs. Although being considered as a first line drug in different types of cancers, the two main obstacles to doxorubicin therapy are drug-induced cardiotoxicity and drug resistance. METHOD: The study utilizes systemic reviews on publications of previous studies obtained from scholarly journal databases including PubMed, Medline, Ebsco Host, Google Scholar, and Cochrane. The study utilizes secondary information obtained from health organizations using filters and keywords to sustain information relevancy. The study utilizes information retrieved from studies captured in the peer-reviewed journals on "doxorubicin-induced cardiotoxicity" and "doxorubicin resistance." DISCUSSION AND RESULTS: The exact mechanisms of cardiotoxicity are not known; various hypotheses are studied. Doxorubicin can lead to free radical generation in various ways. The commonly proposed underlying mechanisms promoting doxorubicin resistance are the expression of multidrug resistance proteins as well as other causes. CONCLUSION: In this review, we have described the major obstacles to doxorubicin therapy, doxorubicin-induced cardiotoxicity as well as the mechanisms of cancer drug resistance and in following the treatment failures.

Modulation of doxorubicin-induced expression of the multidrug resistance gene in breast cancer cells by diltiazem and protection against cardiotoxicity in experimental animals.

BACKGROUND: Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX. METHODS: This study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 µg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats. RESULTS: We found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group. CONCLUSIONS: Taken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.

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

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

Phylogenetic analysis of env gene of bovine leukemia virus strains spread in Miyazaki prefecture, Japan.

To understand how the latest dominant bovine leukemia virus (BLV) strains were introduced and spread in the Miyazaki prefecture, we collected blood samples from 3 geographic areas (north, central and south) and carried out sequence analysis of the BLV env gene. Two genotypes, genotype I, and III, were identified and the majority of the strains belonged to genotype I (71/74). To clarify a route of BLV introduction, we divided the strains into 20 subgenotypes based on their nucleotide sequences and performed phylogenetic analysis. Our study indicated that common BLV strains were comparatively evenly distributed even in the area, where the farmers have not introduced cattle from other areas and the cattle have limited exposure to BLV infection in grazing fields.

Dilemmas of the causality assessment tools in the diagnosis of adverse drug reactions.

IMPORTANCE: Basic essence of Pharmacovigilance is prevention of ADRs and its precise diagnosis is crucially a primary step, which still remains a challenge among clinicians. OBJECTIVE: This study is undertaken with the objective to scrutinize and offer a notion of commonly used as well as recently developed methods of causality assessment tools for the diagnosis of adverse drug reactions and discuss their pros and cons. EVIDENCE REVIEW: Overall 49 studies were recognized for all assessment methods with five major decisive factors of causality evaluation, all the information regarding reasons allocating causality, the advantages and limitations of the appraisal methods were extracted and scrutinized. FINDINGS: From epidemiological information a past prospect is designed and subsequent possibility merged this background information with a clue in the individual case to crop up with an approximation of causation. Expert judgment is typically based on the decisive factor on which algorithms are based, nevertheless in imprecise manner. The probabilistic methods use the similar principle; however connect probabilities to each measure. Such approaches are quite skeptical and liable to generate cloudy causation results. Causation is quite intricate to ascertain than correlation in Pharmacovigilance due to numerous inherent shortcomings in causality assessment tools. CONCLUSIONS AND RELEVANCE: We suggest that there is a need to develop a high quality assessment tool which can meticulously establish suitable diagnostic criteria for ADRs with universal acceptance to improvise the fundamental aspect of drug safety and evade the impending ADRs with the motive to convert Pharmacovigilance into a state of art.

Dibutyl phthalate induces oxidative stress and impairs spermatogenesis in adult rats.

Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely used derivative in various consumer products and medical devices. This study was conducted to further explore the potential testicular toxicity of DBP in adult rats and to elucidate the underlying mechanisms. Adult male albino rats were treated orally with DBP at doses of 0, 200, 400, or 600 mg/kg/day for 15 consecutive days. Testicular weight, sperm count, and motility were significantly decreased. Treatment with DBP decreased serum follicle-stimulating hormone and testosterone levels and testicular lactate dehydrogenase activity. DBP treatment also decreased serum total antioxidant capacity and the activities of the testicular antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase. Further, DBP treatment provoked degeneration with absence of spermatogenesis and sperms and necrosis in some of seminiferous tubules. These results indicated that oxidative stress and subsequent decrease in testosterone secretion were the potential underlying mechanism of DBP-induced testicular toxicity.

Detection of adverse drug reactions by medication antidote signals and comparison of their sensitivity with common methods of ADR detection.

OBJECTIVE: To determine the PPVs of selected ten medication antidote signals in recognizing potential ADRs and comparison of their sensitivity with manual chart analysis, and voluntary reporting recognizing the same ADRs. METHOD: The inpatient EMR database of internal medicine department was utilized for a period of one year, adult patients prescribed at least one of the ten signals, were included in the study, recipient patients of antidote signals were assessed for the occurrence of an ADR by Naranjo's tool of ADR evaluation. PPVs of each antidote signal were verified. RESULT: PPV of Methylprednisolone and Phytonadione was 0.28, Metoclopramide and Potassium Chloride - 0.29, Dextrose 50%, Promethazine, Sodium Polystyrene and Loperamide - 0.30, Protamine and Acetylcysteine - 0.33. In comparison of confirmed ADRs of antidote signals with other methods, Dextrose 50%, Metoclopramide, Sodium Polystyrene, Potassium Chloride, Methylprednisolone and Promethazine seem to be extremely significant (P value > 0.0001), while ADRs of Phytonadione, Protamine, Acetylcysteine and Loperamide were insignificant. CONCLUSION: Antidote medication signals have definitive discerning evaluation value of ADRs over routine methods of ADR detection with a high detection rate with a minimum cost; Their integration with hospital EMR database and routine patient safety surveillance enhances transparency, time-saving and facilitates ADR detection.

Dimethylsulfoxide excerbates cisplatin-induced cytotoxicity in Ehrlich ascites carcinoma cells.

BACKGROUND: Cisplatin (CIS) is a potent antineoplastic agent with high therapeutic efficacy against many kinds of tumors. Its use is limited by its nephrotoxicity. The aim of this work was to minimize cisplatin effective dose and the possible reduction of its severe side effects. The present study was designed to assess the role of sulfur containing agent dimethyl sulfoxide (DMSO) on sensitization of mammary carcinoma, Ehrlich ascites carcinoma (EAC), to the action of cisplatin and at the same time the possible protective effect against cisplatin induced nephrotoxicity in experimental animals. METHODS: To evaluate these effects we have explored the cisplatin effect on the survival time of tumor-bearing animals, tumor weight, cisplatin cellular uptake, apoptosis induction and cell cycle distribution and renal function in presence and absence of DMSO. RESULTS: Cisplatin at dose of 4.5 mg/kg increased the mean survival time of tumor bearing mice to 37 days compared with tumor bearing control mice. Pretreatment of tumor bearing mice with DMSO 50 % (2 ml/kg equal to 1 gm/kg) 2 h. before cisplatin showed a significant increase in their mean survival time 43 days compared to cisplatin treated animals. DMSO pretreatment retained rat's serum urea and creatinine levels to normal compared to animals treated with cisplatin alone. CONCLUSION: DMSO pretreatment enhanced the cytotoxic activity of cisplatin against the growth of EAC in vivo and showed protective effects against cisplatin-induce nephrotoxicity.

Perceptions and knowledge regarding antimicrobial stewardship among clinicians in Jeddah, Saudi Arabia.

OBJECTIVES: To understand the perceptions, attitude, and prescribing practices of clinicians regarding antimicrobial resistance (AMR). METHODS: A multidisciplinary cross-sectional study comprising 447 clinicians of university, public, and private hospitals of Jeddah, Saudi Arabia was carried out from August to October 2014 using a self-administered questionnaire. RESULTS: Interestingly, 33% of the general physicians yielded to patient/parent's demand for the choice of antimicrobials (AMs) as compared with only 13.2% of the residents, and 4.3% of the specialists. In addition, expensive AMs are more often prescribed by the general physician (70.4%) in comparison with 26.4% residents and 30.4% of the specialists. However, no significant differences were observed between the knowledge and perceptions regarding the current scope of AM agents, as well as their use and misuse. Furthermore, dependability of specialist and residents seems to be significantly higher than general physicians on pocketbooks and smartphone for AM education sources. CONCLUSION: This study revealed that despite a clear concept of AMR, general physicians lacks consistency in prescribing aptitude and use of effective educational resources, while all respondents lacks dedication to follow the guidelines of AM use. This highlights the requirement of AM stewardship with decisive objective of reduction in AMR.

Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells.

Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS-resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5-trihydroxy-trans-stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti-inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS-resistant HCT-116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 µg/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 µg/ml). RSVL treatment showed anti-proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS-resistant HCT-116 CRC cells, with a half maximal inhibitory concentration of 4.20 µg/ml and 4.72 µg/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS-resistant HCT-116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS-resistant HCT-116 CRC cells.

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.

Acylated pregnane glycosides from Caralluma quadrangula.

In a previous study, the methanolic extract as well as the chloroform fraction of the aerial parts of Caralluma quadrangula (Forssk.) N.E.Br. indigenous to Saudi Arabia showed significant in vitro cytotoxic activity against breast cancer (MCF7) cell line. In a biologically-guided fractionation approach, four acylated pregnane glycosides were isolated from the chloroform fraction of C. quadrangula. The structures of the isolated compounds were elucidated by the analysis of their MS and NMR data. The compounds were identified as 12,20-di-O-benzoylboucerin 3-O-ß-D-digitoxopyranosyl-(1→4)-ß-D-canaropyranosyl-(1→4)-ß-D-cymaropyranoside (1), 12,20-di-O-benzoylboucerin 3-O-ß-D-cymaropyranosyl-(1→4)-ß-D-canaropyranosyl-(1→4)-ß-D-cymaropyranoside (2), 12,20-di-O-benzoylboucerin 3-O-ß-D-glucopyranosyl-(1→4)-ß-D-digitoxopyranosyl-(1→4)-ß-D-canaropyranosyl-(1→4)-ß-D-cymaropyranoside (3) and 12,20-di-O-benzoyl-3ß,5α,12ß,14ß,20-pentahydroxy-(20R)-pregn-6-ene 3-O-ß-D-glucopyranosyl-(1→4)-ß-D-digitoxopyranosyl-(1→4)-ß-D-canaropyranosyl-(1→4)-ß-D-cymaropyranoside (4). The isolated compounds were tested for their cytotoxic activity against breast cancer (MCF7) cell line.

Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line.

BACKGROUND: Breast cancer is the most common cancer in the Arab world and it ranked first among Saudi females. Doxorubicin (DOX), an anthracycline antibiotic is one of the most effective anticancer agents used to treat breast cancer. chronic cardiotoxicity is a major limiting factor of the use of doxorubicin. Therefore, our study was designed to assess the role of a natural product resveratrol (RSVL) on sensitization of human breast cancer cells (MCF-7) to the action of DOX in an attempt to minimize doxorubicin effective dose and thereby its side effects. METHODS: Human breast cancer cell line MCF-7, was used in this study. Cytotoxic activity of DOX was determined using (sulforhodamine) SRB method. Apoptotic cells were quantified after treatment by annexin V-FITC- propidium iodide (PI) double staining using flow-cytometer. Cell cycle disturbance and doxorubicin uptake were determined after RSVL or DOX treatment. RESULTS: Treatment of MCF-7 cells with 15 µg/ml RSVL either simultaneously or 24 h before DOX increased the cytotoxicity of DOX, with IC50 were 0.056 and 0.035 µg/ml, respectively compared to DOX alone IC50 (0.417 µg/ml). Moreover, flow cytometric analysis of the MCF-7 cells treated simultaneously with DOX (0.5 µg/ml) and RSVL showed enhanced arrest of the cells in G0 (80%). On the other hand, when RSVL is given 24 h before DOX although there was more increased in the cytotoxic effect of DOX against the growth of the cells, however, there was decreased in percentage arrest of cells in G0, less inhibition of DOX-induced apoptosis and reduced DOX cellular uptake into the cells. CONCLUSION: RSVL treatment increased the cytotoxic activity of DOX against the growth of human breast cancer cells when given either simultaneously or 24 h before DOX.