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Nilotpal Roy,
Prashant V Bommi,
Uppoor G Bhat,
Shaumick Bhattacharjee,
Indira Elangovan, Jing Li,
Krushna C Patra,
Dragana Kopanja,
Adam Blunier,
Richard V Benya,
Srilata Bagchi,
Pradip Raychaudhuri
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ABSTRACT: Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial to mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here we show that the xeroderma pigmentosum group E (XPE) gene product DDB2 is down-regulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.
Cancer Research 04/2013; · 7.86 Impact Factor
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Zebin Wang,
Yu Zheng,
Hyun Jung Park, Jing Li,
Janai R Carr,
Yi-Ju Chen,
Megan M Kiefer,
Dragana Kopanja,
Srilata Bagchi,
Angela L Tyner,
Pradip Raychaudhuri
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ABSTRACT: The forkhead box transcription factor FOXM1 is considered to be a promising target for cancer therapy. However, the significance of FOXM1 in tumors harboring mutation in p53, which is very common, is unclear. In this study, we investigated the efficacy of FoxM1-targeting in spontaneous p53-null tumors using genetic ablation as well as using a peptide-inhibitor of FOXM1. We show that conditional deletion of FoxM1 inhibits growth of the p53 null thymic lymphoma and sarcoma cells. In addition, deletion of FoxM1 induces apoptotic cell death of the p53 null tumors, accompanied by reduced expression of the FOXM1 target genes Survivin and Bmi1. An ARF-derived peptide that inhibits the activity of FOXM1, by targeting it to the nucleolus, also induces apoptosis in the p53 null sarcoma and lymphoma, leading to a strong inhibition of their metastatic colonization. Together, our observations suggest that FOXM1 is critical for survival and growth of the p53-null lymphoma and sarcoma, and provide proof-of-principle that FOXM1 is an effective therapeutic target for sarcoma and lymphoma carrying loss of function mutation in p53.
Molecular Cancer Therapeutics 02/2013; · 5.23 Impact Factor
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ABSTRACT: Mammary sarcoma is extremely rare and the diagnosis is established only after metaplastic carcinomas and malignant phyllodes tumours are excluded. A rare case of not otherwise specified-type sarcoma with CD10 expression in the left breast in a 45-year-old female was presented. It was a high-grade tumour composed of spindle cells histologically. The immunohistochemical results showed that CD10, vimentin and EGFR were positive diffusely and SMA presented focally, whereas epithelial markers and other myoepithelial or myogenic markers were all negative. The electron microscope investigation demonstrated fibroblastlike features. The exact entity of the tumour remained to be studied because it resembles undifferentiated sarcoma or sarcomatoid metaplastic carcinoma to some degree, as well as high-grade malignant phyllodes tumour in particular. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9019879588725702.
Diagnostic Pathology 01/2013; 8(1):14. · 1.64 Impact Factor
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Wei-Tien Chang, Jing Li,
Matthew S Vanden Hoek,
Xiangdong Zhu,
Chang-Qing Li,
Hsien-Hao Huang,
Chin-Wang Hsu,
Qiang Zhong,
Juan Li,
Sy-Jou Chen,
Terry L Vanden Hoek,
Zuo-Hui Shao
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ABSTRACT: Previous studies suggest baicalein, in addition to its antioxidant effects, protects against hypoxia/reoxygenation injury via its pro-oxidant properties. We hypothesize that a brief period of baicalein treatment prior to ischemia/reperfusion (I/R) may trigger preconditioning protection via a mitochondrial pro-oxidant mechanism. Using an established chick cardiomyocyte model of I/R, cells were preconditioned with baicalein (10 μM) for 10 min followed by 10-min wash prior to I/R. Intracellular oxidants were measured using 2', 7'-dichlorofluorescin diacetate (DCFH/DA). Cell viability was assessed by propidium iodide and apoptosis determined by DNA fragmentation. Baicalein induced a transient but significant increase of DCF fluorescence within the 10-min preconditioning period, and led to significant reduction of cell death (38.9 ± 1.8% vs. 58.7 ± 1.2% in I/R control, n = 6, p < 0.001) and DNA fragmentation after I/R. Cotreatment with N-acetylcysteine (500 μM), mitochondrial complex III electron transport chain inhibitor myxothiazol (1 μM), mitochondrial KATP channel blocker 5-hydroxydecanoate-Na (5-HD, 500 μM) or anion channel inhibitor 4', 4'-diisothiocyanato-stilbene-2, 2'-disulfonic acid (DIDS, 200 μM) resulted in significant abrogation of oxidant increase during induction as well as the protection conferred by baicalein preconditioning. These results suggest that baicalein preconditioning exhibits significant anti-apoptotic protection against cardiomyocyte I/R injury by mitochondrial oxidant signaling, which was in part mediated by mitochondrial KATP channel and anion channel opening.
The American Journal of Chinese Medicine 01/2013; 41(2):315-31. · 1.98 Impact Factor
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ABSTRACT: Herein is reported, for the first time, a simple and highly sensitive chiral high-performance liquid chromatography (HPLC) method for the simultaneous quantitative determination of difenoconazole stereoisomers and their hydroxylated metabolite difenoconazole alcohol (CGA-205375) enantiomers in vegetables and soil matrix. The separation of difenoconazole and CGA-205375 including their simultaneous enantioseparation was studied using four different polysaccharide-type chiral stationary phases (CSPs) in combination with n-hexane-polar organic alcohols mobile phase. Chiralcel OJ consisting of 25 % of cellulose tris(4-methylbenzoate) coated on wide-pore polysaccharide silica gel exhibited higher resolving ability compared to cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD) as well as to its similar amylose derivative (Chiralpak AD) CSPs for this particular set of chiral analytes. Baseline separation and simultaneous enantioseparation of difenoconazole and its metabolite CGA-205375 could be achieved under optimized separation conditions. Based on the established HPLC method, enantioselective analysis method for this fungicide and its main chiral metabolite in vegetables and soil matrix were developed and validated. Parameters including the matrix effect, linearity, precision, accuracy, and stability were evaluated. Under the optimal conditions, the mean recoveries from cucumber, tomato, and soil matrix ranged from 81.65 to 94.52 %, with relative standard deviations in the range of 1.05-8.32 % for all stereoisomers. Coefficients of determination R (2) ≥ 0.998 were achieved for each enantiomer in the cucumber, tomato and soil matrix calibration curves within the range of 0.5-50 μg mL(-1). The limits of quantification for all enantiomers in three matrices were all below 0.1 μg mL(-1). The methodology was successfully applied for simultaneous enantioselective analysis of difenoconazole stereoisomers and their metabolite in the real samples, indicating its efficacy in investigating the environmental stereochemistry of difenoconazole in food and environmental matrix.
Analytical and Bioanalytical Chemistry 08/2012; 404(6-7):2017-31. · 3.78 Impact Factor
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ABSTRACT: For glass slides covered by two-dimensional array of polystyrene spheres with Au nanocaps on the top surface, polar Kerr rotation θ(K) peaks occur in the visible region and shift with the polystyrene sphere diameter. The θ(K) spectra arise from the spectral properties of the transmission/reflectance ratio. The observed tunable magneto-optical behavior has potential applications in magneto-optical filters.
Applied Optics 08/2012; 51(23):5713-7. · 1.41 Impact Factor
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ABSTRACT: Type 2C protein phosphatases (PP2C) are monomeric enzymes that require magnesium or manganese ions for their activities. There are seven PP2C genes in Candida albicans. Here, we demonstrate that CaPTC5 encodes a mitochondrial PP2C enzyme. Expression of CaPTC5 transcripts remains constant during the serum-induced hyphal development. Deletion of CaPTC5 does not affect the in vitro filamentation but renders C. albicans cells sensitive to terbinafine and cadmium, and this sensitivity is complemented by the Saccharomyces cerevisiae ScPTC5. Deletion of CaPTC6 does not have any additive effect on, but deletion of CaPTC7 blocks, the terbinafine sensitivity owing to deletion of CaPTC5. In addition, we have shown that deletion of CaPTC6 also renders C. albicans cells sensitive to cadmium, while deletion of CaPTC7 leads to a high cadmium tolerance, and this tolerance is abolished by further deletion of CaPTC5 or CaPTC6. Furthermore, double deletion of CaPTC6 and CaPTC7 renders C. albicans cells more tolerant to azoles, but deletion of CaPTC5 and CaPTC7 slightly increases the azole sensitivity of C. albicans cells. Our results demonstrate that three mitochondrial PP2C genes CaPTC5, CaPTC6 and CaPTC7 interact differentially in the response of C. albicans cells to antifungal drugs and cadmium.
FEMS Yeast Research 08/2012; · 2.40 Impact Factor
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ABSTRACT: This paper describes a non-homogeneous distributed storage systems (DSS),
where there is one super node which has a larger storage size and higher
reliability and availability than the other storage nodes. We propose three
distributed storage schemes based on (k+2; k) maximum distance separable (MDS)
codes and non-MDS codes to show the efficiency of such non-homogeneous DSS in
terms of repair efficiency and data availability. Our schemes achieve optimal
bandwidth (k+1/2)(M/k) when repairing 1-node failure, but require only one
fourth of the minimum required file size and can operate with a smaller field
size leading to significant complexity reduction than traditional homogeneous
DSS. Moreover, with non-MDS codes, our scheme can achieve an even smaller
repair bandwidth of M/2k . Finally, we show that our schemes can increase the
data availability by 10% than the traditional homogeneous DSS scheme.
08/2012;
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ABSTRACT: In tonal languages such as Mandarin Chinese, suprasegmental tones are used to signal word meaning besides consonants and vowels. To reveal memory traces for tonal language words, we presented native Mandarin Chinese speakers with a sequence of spoken syllables as standards and disyllables as deviants in a passive oddball paradigm. The second syllable of each disyllable carried critical tonal information that would define the disyllable either as a meaningful word or as a meaningless pseudoword. The words and pseudowords were acoustically and phonologically matched as well as counterbalanced. The auditory event-related potential in response to words was more negatively deflected than that in response to pseudowords. This effect was most prominent 164 ms after the word recognition point. Our study indicates an activation of memory traces for tonal language words.
Psychophysiology 08/2012; 49(10):1353-60. · 3.29 Impact Factor
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ABSTRACT: A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, and select tertiary alcohols without the need for an excess of either coupling partner. This catalyst system displays broad functional-group tolerance and excellent regioselectivity, and is insensitive to the order of reagent addition.
Angewandte Chemie International Edition 08/2012; 51(36):9071-4. · 13.45 Impact Factor
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Janai R Carr,
Megan M Kiefer,
Hyun Jung Park, Jing Li,
Zebin Wang,
Joel Fontanarosa,
Danielle DeWaal,
Dragana Kopanja,
Elizaveta V Benevolenskaya,
Grace Guzman,
Pradip Raychaudhuri
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ABSTRACT: Elevated expression of FoxM1 in breast cancer correlates with an undifferentiated tumor phenotype and a negative clinical outcome. However, a role for FoxM1 in regulating mammary differentiation was not known. Here, we identify another function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown of FoxM1 results in a shift toward the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers.
Cell reports. 06/2012; 1(6):715-29.
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ABSTRACT: In 1987, Carney et al described a rare thyroid tumor termed hyalinizing trabecular adenoma presenting characteristics consisting of a trabecular growth pattern and hyalinizing stroma. In subsequent reports, the observed nuclear features and RET alterations led this tumor to be linked to papillary carcinoma. Subsequent reports concerning hyalinizing trabecular carcinoma further complicated its classification. To avoid uncertainties, the definition of hyalinizing trabecular tumor (HTT) is more widely used. Herein, a case of HTT is reported in detail, and the circumstances are also discussed. HTT is thought to be particularly differentiated from papillary carcinoma despite the identical high frequency of nuclear grooves and cytoplasmic inclusions, and MIB-1-positive staining is one of the most accurate diagnostic methods due to the distinct membrane-positive pattern noted in HTT. It is believed that most HTTs are benign and lobectomy is the standard treatment. Pathologists should offer surgeons information concerning diagnosis overlapping with effective treatment.
Experimental and therapeutic medicine 06/2012; 3(6):1015-1017.
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ABSTRACT: To investigate the pathologic and immunohistochemical features, diagnosis and differential diagnosis of low-grade adenosquamous carcinoma of the breast and syringomatous adenoma of the nipple.
Six cases of low-grade adenosquamous carcinoma of the breast and four cases of syringomatous adenoma of the nipple were examined histologically and immunohistochemically (MaxVision method), and the literature was reviewed.
The two types of tumors were similar in morphology, but located in different regions with low-grade adenosquamous carcinoma being present in the deep parenchyma and syringomatous adenoma in nipple. Both types of tumors were composed mainly of well-differentiated glands with angulated, comma shaped or polliwog appearance in a disordered infiltrative pattern. The tumor cells also formed solid tubules, strips or nests, with frequent areas of squamoid differentiation. Mitosis was rare. The interstitial tissue showed abundant spindle cells or sclerotic fibrosis with mixed inflammatory cells infiltration. One case of low-grade adenosquamous carcinoma showed a concomitant malignant adenomyoepithelioma, and another case showed concomitant spindle cell metaplastic carcinoma. One case of syringomatous adenoma involved the deep parenchyma. Immunohistochemistry of low-grade adenosquamous carcinoma showed that CK5/6 and p63 were positive in the outer layer of the glands and the squamoid epithelium, and CD10 was also positive in the outer layer of the glands. ER and HER2 were negative, and PR was also negative except for one case in which the spindle cells were positive for CK5/6, AE1/AE3 and PR focally. Immunostaining of syringomatous adenoma demonstrated that p63 and CK5/6 were positive in the outer layer of the glands and the squamoid epithelium. Calponin, SMA, ER, PR and HER2 were all negative.
Low-grade adenosquamous carcinoma of the breast and syringomatous adenoma of the nipple are similar in morphology and immunohistochemical phenotype, while the biological features are opposite due to different locations. The differential diagnoses include tubular carcinoma, adenosquamous carcinoma, radial sclerosing lesions and others.
Zhonghua bing li xue za zhi Chinese journal of pathology 05/2012; 41(5):301-4.
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ABSTRACT: Malignant neuroblastomas contain stem-like cells. These tumors also overexpress the Forkhead box transcription factor FoxM1. In this study, we investigated the roles of FoxM1 in the tumorigenicity of neuroblastoma. We showed that depletion of FoxM1 inhibits anchorage-independent growth and tumorigenicity in mouse xenografts. Moreover, knockdown of FoxM1 induces differentiation in neuroblastoma cells, suggesting that FoxM1 plays a role in the maintenance of the undifferentiated progenitor population. We showed that inhibition of FoxM1 in malignant neuroblastoma cells leads to the downregulation of the pluripotency genes sex determining region Y box 2 (Sox2) and Bmi1. We provided evidence that FoxM1 directly activates expression of Sox2 in neuroblastoma cells. By using a conditional deletion system and neurosphere cultures, we showed that FoxM1 is important for expression of Sox2 and Bmi1 in the mouse neural stem/progenitor cells and is critical for its self-renewal. Together, our observations suggested that FoxM1 plays an important role in the tumorigenicity of the aggressive neuroblastoma cells through maintenance of the undifferentiated state.
Cancer Research 06/2011; 71(12):4292-302. · 7.86 Impact Factor
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Wei-Tien Chang, Jing Li,
Hsien-Hao Haung,
Huiping Liu,
Mei Han,
Srinivasan Ramachandran,
Chang-Qing Li,
Willard W Sharp,
Kimm J Hamann,
Chun-Su Yuan,
Terry L Vanden Hoek,
Zuo-Hui Shao
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ABSTRACT: The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. We therefore investigated if baicalein, a natural antioxidant component of Scutellaria baicalensis, could attenuate ROS generation and cell death induced by doxorubicin. Using an established chick cardiomyocyte model, doxorubicin (10 µM) increased cell death in a concentration- and time-dependent manner. ROS generation was increased in a dose-response fashion and associated with loss of mitochondrial membrane potential. Doxorubicin also augmented DNA fragmentation and increased the phosphorylation of ROS-sensitive pro-apoptotic kinase c-Jun N-terminal kinase (JNK). Adjunct treatment of baicalein (25 µM) and doxorubicin for 24 h significantly reduced both ROS generation (587 ± 89 a.u. vs. 932 a.u. ± 121 a.u., P < 0.01) and cell death (30.6 ± 5.1% vs. 46.8 ± 8.3%, P < 0.01). The dissipated mitochondrial potential and increased DNA fragmentation were also ameliorated. Along with the reduction of ROS and apoptosis, baicalein attenuated phosphorylation of JNK induced by doxorubicin (1.7 ± 0.3 vs. 3.0 ± 0.4-fold, P < 0.05). Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 µM; 24 h) reduced JNK phosphorylation and enhanced cell survival, suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Importantly, concurrent baicalein treatment did not interfere with the anti-proliferative effects of doxorubicin in human breast cancer MCF-7 cells. In conclusion, baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy.
Journal of Cellular Biochemistry 05/2011; 112(10):2873-81. · 2.87 Impact Factor
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Hyun Jung Park,
Galina Gusarova,
Zebin Wang,
Janai R Carr, Jing Li,
Ki-Hyun Kim,
Jin Qiu,
Yoon-Dong Park,
Peter R Williamson,
Nissim Hay,
Angela L Tyner,
Lester F Lau,
Robert H Costa,
Pradip Raychaudhuri
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ABSTRACT: The forkhead box M1b (FoxM1b) transcription factor is over-expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over-expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf-null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial-mesenchymal transition, cell motility, invasion and a pre-metastatic niche formation. FoxM1b activates the Akt-Snail1 pathway and stimulates expression of Stathmin, lysyl oxidase, lysyl oxidase like-2 and several other genes involved in metastasis. Furthermore, we show that an Arf-derived peptide, which inhibits FoxM1b, impedes metastasis of the FoxM1b-expressing HCC cells. The observations indicate that FoxM1b is a potent activator of tumour metastasis and that the Arf-mediated inhibition of FoxM1b is a critical mechanism for suppression of tumour metastasis.
EMBO Molecular Medicine 01/2011; 3(1):21-34. · 10.33 Impact Factor
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ABSTRACT: Multicomponent reactions are employed extensively in many areas of organic chemistry. Despite significant progress, the discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free reaction-discovery platform that can be used in the identification of new multicomponent transformations. Our approach is based on parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers. This strategy enabled the identification of a simple organic phosphine that can catalyse a previously unknown condensation of siloxyalkynes, aldehydes and amines to produce 3-hydroxyamides with high efficiency and diastereoselectivity. The reaction was further optimized using solution-phase methods.
Nature Chemistry 01/2011; 4(1):45-51. · 20.52 Impact Factor
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ABSTRACT: This paper describes a model system to characterize the rate enhancement that stems from localization of an enzyme with its substrate. The approach is based on a self-assembled monolayer that presents a substrate for the serine esterase cutinase along with a peptide ligand for an SH2 adaptor domain. The monolayer is treated with a fusion protein of cutinase and the SH2 domain, and the rate for the interfacial reaction is monitored using cyclic voltammetry. The rate is approximately 30-fold greater for monolayers that present the ligand for the SH2 domain than for those that omit the ligand. The rate enhancement is due to the interaction of the adaptor domain with the immobilized ligand. Further, the rate enhancement increases with the densities of both the ligand and the substrate. This example provides a well-defined model system for quantitatively assessing the magnitude of rate enhancement that is possible with colocalization of an enzyme with its substrate and may be particularly significant for understanding the signaling events that rely on enzyme localization at the cell membrane.
The Journal of Physical Chemistry B 11/2010; 114(46):15113-8. · 3.70 Impact Factor
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ABSTRACT: Cytokine production during hemorrhagic shock (HS) could affect cardiac function during the hours after resuscitation. Visfatin is a recently described protein that functions both as a proinflammatory plasma cytokine and an intracellular enzyme within the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway. We developed a mouse model of HS to study the effect of therapeutic hypothermia (TH) on hemodynamic outcomes and associated plasma and tissue visfatin content.
Mice were bled and maintained at a mean arterial pressure (MAP) of 35 mmHg. After 30 min, animals (n=52) were randomized to normothermia (NT, 37+/-0.5 degrees C) or TH (33+/-0.5 degrees C) followed by rewarming at 60 min following resuscitation. After 90 min of HS (S90), mice were resuscitated and monitored for 180 min (R180). Visfatin, interleukin 6 (IL-6), keratinocyte-derived chemokine (KC), tumor necrosis factor-alpha (TNF-alpha), and myoglobin were measured by ELISA.
Compared to NT, TH animals exhibited improved R180 survival (23/26 [88.5%] vs. 13/26 [50%]; p=0.001). Plasma visfatin, IL-6, KC, and TNF-alpha increased by S90 in both groups (p<0.05). TH attenuated S90 plasma visfatin and, after rewarming, decreased R180 plasma IL-6, KC, and myoglobin (p<0.05) relative to NT. Heart and gut KC increased at S90 while IL-6 increases were delayed until R180 (p<0.05). NT produced sustained elevations of myocardial KC but decreased visfatin by R180, effects abrogated by TH (p<0.05).
In a mouse model of HS, TH improves hemodynamics and alters plasma and tissue proinflammatory cytokines including the novel cytokine visfatin. TH modulation of cytokines may attenuate cardiac dysfunction following HS.
Resuscitation 03/2010; 81(6):742-8. · 3.60 Impact Factor
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Jing Li,
Huiping Liu,
Srinivasan Ramachandran,
Gregory B Waypa,
Jun-Jie Yin,
Chang-Qing Li,
Mei Han,
Hsien-Hao Huang,
Willard W Sillard,
Terry L Vanden Hoek,
Zuo-Hui Shao
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ABSTRACT: Doxorubicin (Dox) is one of the most widely used and successful chemotherapeutic antitumor drugs. Its clinical application is highly limited due to its cumulative dose-related cardiotoxicity. Proposed mechanisms include the generation of reactive oxygen species (ROS)-mediated oxidative stress. Therefore, reducing oxidative stress should be protective against Dox-induced cardiotoxicity. To determine whether antioxidant, grape seed proanthocyanidin extract (GSPE) attenuates Dox-induced ROS generation and protects cardiomyocytes from Dox-induced oxidant injury, cultured primary cardiomyocytes were treated with doxorubicin (Dox, 10 microM) alone or GSPE (50 microg/ml) with Dox (10 microM) for 24 hours. Dox increased intracellular ROS production as measured by 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, induced significant cell death as assessed by propidium iodide, and declined the redox ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) and disrupted mitochondrial membrane potential as determined by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethlbenzimidazole-carbocyanide iodine (JC-1). Analysis of agarose gel electrophoresis revealed Dox-induced nuclear DNA damage with the ladder like fragmentation. GSPE treatment suppressed those alterations. Electron Spin Resonance (ESR) spectroscopy data also showed that GSPE strongly scavenged hydroxyl radical, superoxide and DPPH radicals. Together, these findings indicate that GSPE in combination with Dox has protective effect against Dox-induced toxicity in cardiomyocytes, which may be in part attributed to its antioxidative activity. Importantly, flow cytometric analysis demonstrated that co-treatment of Dox and GSPE did not decrease the proliferation-inhibitory effect of Dox in MCF-7 human breast carcinoma cells. Thus, GSPE may be a promising adjuvant to prevent cardiotoxicity without interfering with antineoplastic activity during chemotherapeutic treatment with Dox.
The American Journal of Chinese Medicine 01/2010; 38(3):569-84. · 1.98 Impact Factor
