The Experts below are selected from a list of 1353 Experts worldwide ranked by ideXlab platform
George A Odoherty - One of the best experts on this subject based on the ideXlab platform.
-
abstract 3205 structural analysis of cardiac glycosides to determine the basis for tumoristatic activity
Cancer Research, 2014Co-Authors: Vivek Kaushik, George A Odoherty, Yogesh Kaulkarni, Clayton Wright, Neelam Azad, Anand Krishnan V IyerAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Cardiac glycosides (cardenolides) such as Digitoxin are routinely used in the clinic to treat arrhythmias; recent studies however have delved into their potential as anti-cancer agents. One major concern with the use of cardenolides is their narrow therapeutic index, which precludes their use in oncology due to the higher doses required to achieve tumoristatic effects. However, synthesis of chemical analogs of cardenolides with much higher anti-tumor efficacy whilst maintaining the pathway-specificities of their parent compounds is highly desirable. Our group has previously developed a patented palladium-catalyzed de novo synthesis methodology for synthesis of complex carbohydrates, which has allowed us to synthesize a library of Digitoxin analogues. One novel non-natural monosaccharide derivative (β-D-Digitoxin or MonoD) in particular demonstrates strong cytotoxic effects on a wide variety of tumors as assessed by measuring activity against the NCI panel of 60 cancer cell lines. More importantly, MonoD exerts at least a five-fold higher tumoristatic effect as compared to Digitoxin. As opposed to Digitoxin that has three sugar moieties (trisaccharide) attached to a steroid domain, MonoD is a monosaccharide with only one sugar unit. This suggests that the length of the sugar side chain may play a critical role in determining anti-cancer efficacy of cardenolides. Furthermore, our preliminary work suggests that the nature of substituents on both the carbohydrate and steroid portions of Digitoxin affects its efficacy. In order to further delineate the basis for such differential effects, we selected three naturally occurring cardenolides that have similar structures to that of MonoD with variations in either the sugar region, the steroid unit or both - Convallatoxin (CV), Peruvoside (PV) and Cymarin (CM) - and assessed for tumoristatic effects. Our preliminary data shows that differences in functional groups can have direct effects on the efficacy of cardenolides in exerting tumoristatic effects. All the selected cardenolides demonstrated potent inhibition of cell viability as assessed by availability of functional ATP using Cell Titer Glo®. Confounding however was the fact that unlike naturally occurring cardenolides, increasing amounts of MonoD led to increased availability of ATP. However, apoptosis assays clearly indicated that MonoD did lead to cell death. We will be pursuing further structural modification analysis to determine the underlying cause of such differential effects. A SAR study to delineate specific variations in the substituents in both the sugar and the steroid unit of cardenolides may help access compounds that have higher anti-tumorigenic potential against cancers. Citation Format: Vivek Kaushik, Yogesh Kaulkarni, Clayton Wright, George O'Doherty, Neelam Azad, Anand Iyer. Structural analysis of cardiac glycosides to determine the basis for tumoristatic activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3205. doi:10.1158/1538-7445.AM2014-3205
-
monosaccharide Digitoxin derivative sensitize human non small cell lung cancer cells to anoikis through mcl 1 proteasomal degradation
Biochemical Pharmacology, 2014Co-Authors: George A Odoherty, Varisa Pongrakhananon, Todd A Stueckle, Hua Yu Leo Wang, Cerasela Zoica Dinu, Pithi Chanvorachote, Yon RojanasakulAbstract:Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, Digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with Digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than Digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and Digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and Digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
-
stereochemical survey of Digitoxin monosaccharides new anticancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non small cell lung cancer cell
ACS Medicinal Chemistry Letters, 2011Co-Authors: Hua Yu Leo Wang, Todd A Stueckle, Yon Rojanasakul, Maoqua Zhou, George A OdohertyAbstract:A stereochemically diverse array of monosaccharide analogues of the trisaccharide-based cardiac glycoside natural product Digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against nonsmall cell human lung cancer cells (NCI-H460). The results were compared with Digitoxin and its aglycone digitoxigenin. Three novel Digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that Digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar antiproliferation effects but with at least 5-fold greater potency in apoptosis induction than Digitoxin against NCI-H460. This study demonstrates the ability to improve the Digitoxin anticancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.
-
a stereoselective synthesis of Digitoxin and digitoxigen mono and bisdigitoxoside from digitoxigenin via a palladium catalyzed glycosylation
Organic Letters, 2006Co-Authors: Maoquan Zhou, George A OdohertyAbstract:A convergent and stereocontrolled route to trisaccharide natural product Digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product Digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.
Camilla Schinner - One of the best experts on this subject based on the ideXlab platform.
-
the inotropic agent Digitoxin strengthens desmosomal adhesion in cardiac myocytes in an erk1 2 dependent manner
Basic Research in Cardiology, 2020Co-Authors: Camilla Schinner, Silvana Olivaresflorez, Angela Schlipp, Sebastian Trenz, Manouk Feinendegen, Heinrich Flaswinkel, Ellen Kempf, Desalegn Tadesse Egu, Sunil YeruvaAbstract:Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive adhesiotropy", was demonstrated to be a function of sympathetic signaling and to be relevant for a sufficient inotropic response. We used the inotropic agent Digitoxin to investigate the link between inotropy and adhesiotropy. In contrast to wild-type hearts, Digitoxin failed to enhance pulse pressure in perfused mice hearts lacking the desmosomal protein plakoglobin which was paralleled with abrogation of plaque thickening indicating that positive inotropic response requires intact desmosomal adhesion. Atomic force microscopy revealed that Digitoxin increased the binding force of the adhesion molecule desmoglein-2 at cell-cell contact areas. This was paralleled by enhanced cardiac myocyte cohesion in both HL-1 cardiac myocytes and murine cardiac slices as determined by dissociation assays as well as by accumulation of desmosomal proteins at cell-cell contact areas. However, total protein levels or cytoskeletal anchorage were not affected. siRNA-mediated depletion of desmosomal proteins abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, Digitoxin caused activation of ERK1/2. In line with this, inhibition of ERK1/2 signaling abrogated the effects of Digitoxin on cell-cell adhesion and desmosomal reorganization. These results show that the positive inotropic agent Digitoxin enhances cardiac myocyte cohesion with reorganization of desmosomal proteins in an ERK1/2-dependent manner. Desmosomal adhesion seems to be important for a sufficient positive inotropic response of Digitoxin treatment, which can be of medical relevance for the treatment of heart failure.
Amitava Dasgupta - One of the best experts on this subject based on the ideXlab platform.
-
the fab fragment of anti digoxin antibody digibind binds Digitoxin like immunoreactive components of chinese medicine chan su monitoring the effect by measuring free Digitoxin
Clinica Chimica Acta, 2001Co-Authors: Amitava Dasgupta, Ana E Lopez, Alice Wells, Margaret Olsen, Jeffrey K ActorAbstract:Abstract Chan Su, a Chinese medicine prepared from the skin glands of Chinese toads, is used in the treatment of cardiovascular diseases. Severe toxicity and even death has been reported from overdose with Chan Su. The cardiotonic effect of Chan Su is attributed to bufadienolides, which also have apparent Digitoxin activity. We demonstrated that these components of Chan Su could be neutralized by digibind, both in vitro and in vivo. For in vitro experiments, we supplemented drug-free serum pools with aqueous extract of Chan Su. Then, to aliquots of serum pool containing Chan Su, various amounts of digibind (10, 25 or 50 μg/ml of serum) were added. After incubation, total and free Digitoxin concentrations (in the protein-free ultrafiltrate) were measured using the fluorescence polarization immunoassay (FPIA) and a FLX/TDx analyzer. For in vivo experiments, mice were fed with Chan Su by gavage. After 45 min, 200 μg of digibind was administered by injection. Fifteen minutes after injection, blood was collected for analysis of total and free apparent Digitoxin activities. We observed complete removal of apparent Digitoxin activity from protein-free ultrafiltrate both in vitro and in vivo by digibind, indicating that digibind successfully binds Chan Su. We conclude that digibind neutralizes Chan Su, and measuring the free Digitoxin concentrations can monitor such an effect.
-
effect of digoxin fab antibody on the measurement of total and free Digitoxin by fluorescence polarization and a new chemiluminescent immunoassay
Therapeutic Drug Monitoring, 1999Co-Authors: Amitava Dasgupta, Alice Wells, Pradip DattaAbstract:Digoxin fab antibody (Digibind; Burroughs Wellcome, Research Triangle Park, NC, USA) is used in the treatment of digoxin overdose. The effect of digibind on the measurement of total and free digoxin has been extensively studied. However, the effect of digibind on Digitoxin measurements has not been studied thoroughly. The authors studied the effect of digibind on the measurement of total and free Digitoxin in vitro using the fluorescence polarization immunoassay and a new chemiluminescent immunoassay. We also studied the capability of digibind to bind digitoxigenin, the major aglycon metabolite of Digitoxin. Digibind neutralized both Digitoxin and digitoxigenin in vitro, as evidenced by significant reductions in free Digitoxin and digitoxigenin (measured as Digitoxin equivalent) concentrations. Digibind caused negative interference in the measurement of total Digitoxin concentrations by both fluorescence polarization and chemiluminescent assays. However, the magnitude of negative interference was significantly higher with the chemiluminescent assay. For example, in a serum pool supplemented with 80 ng/mL of Digitoxin, the concentrations of total and free Digitoxin measured by the fluorescence polarization immunoassay were 82.1 ng/mL and 3.3 ng/mL respectively. In the presence of 5 microg/mL of Digibind, the corresponding total and free Digitoxin concentrations were 73.9 ng/mL and none detected, respectively. In another serum pool supplemented with 70 ng/mL of Digitoxin, the concentrations of total and free Digitoxin as measured by the chemiluminescent assay were 69.1 ng/mL and 3.8 ng/mL, respectively. In the presence of 5 microg/mL of Digibind, the corresponding total and free Digitoxin concentrations were 29.0 ng/mL and none detected, respectively. Because this effect may also occur in vivo, the progress of Digibind therapy in treating a patient with Digitoxin overdose may be monitored by measuring the free Digitoxin concentrations.
-
neutralization of cardiac toxins oleandrin oleandrigenin bufalin and cinobufotalin by digibind monitoring the effect by measuring free Digitoxin concentrations
Life Sciences, 1998Co-Authors: Amitava Dasgupta, Lyska EmersonAbstract:Abstract Oleandrin plant poisoning is common in children and the plant extract is used in Chinese medicines. The toxicity is due to oleandrin and the deglycosylated metabolite oleandrigenin. Bufalin and cinobufotalin (toad cardiac toxins) are also widely used in Chinese medicines like Chan SU, and Lu-Shen -WU. Severe toxicity from bufalin after consumption of toad soup has been reported. Taking advantage of structural similarities of these toxins with Digitoxin, we demonstrated that these compounds can be rapidly detected in blood by the fluorescence polarization immunoassay for Digitoxin. The cross reactivities of these compounds with digoxin assay were much lower. For example, when a drug free serum was supplemented with 10 μg/ml of oleandrin, we observed 127.7 ng/ml of Digitoxin equivalent but only 2.4 ng/ml of digoxin equivalent concentration. Digibind neutralized all cardiac toxins studied as evidenced by significant fall of free concentrations. When aliquots of serum pool containing 50.0 ug/ml of oleandrin were supplemented with 0, 10.0, 25.0, 50.0, 100, and 200 μg/ml of digibind, the mean free concentrations were 30.6, 23.3, 16.0, 10.7, 7.8 and 5.5 μg/ml respectively. Similarly, with 50.0 μg/ml of oleandrigenin (total concentration: 36.2 ng/ml), the free concentration was 14.5 ng/ml Digitoxin equivalent in the absence of digibind and 5.4 ng/ml in the presence of 200 μg/ml of digibind. In another specimen containing 500 ng/ml bufalin (total concentration: 156.9 ng/ml), the free concentration was 8.6 ng/ml in the absence of digibind and none detected in the presence of 100.0 μg/ml digibind. Because such neutralization may also occur in vivo, digibind may be useful in treating patients exposed to these toxins.
-
bidirectional positive negative interference in a digoxin immunoassay importance of antibody specificity
Therapeutic Drug Monitoring, 1998Co-Authors: Pradip Datta, Amitava DasguptaAbstract:The importance of high specificity in immunoassays used in therapeutic monitoring is highlighted by a case study in which therapeutic-to-toxic borderline digoxin levels were measured by a digoxin immunoassay in the serum sample from a patient administered Digitoxin rather than digoxin. The sample, mistakenly sent to the laboratory for digoxin analysis, gave discordant results in three digoxin immunoassays: 1.99 and 0.79 ng/ml in assays using polyclonal antibodies (fluorescence-polarization immunoassay and microparticle enzyme immunoassay, respectively), and <0.1 ng/ml in a chemiluminescent immunoassay using more specific monoclonal antibody. The presence of Digitoxin (approximately 40 ng/ml) in the sample was confirmed by three different Digitoxin immunoassays. Based on these results, the interference of different levels of Digitoxin was studied in the presence of 0, 0.85, 1.9, and 4.7 ng/ml digoxin in all three digoxin assays. The chemiluminescent assay showed no significant interference. The fluorescence-polarization immunoassay showed positive interference in all cases; however, the microparticle enzyme immunoassay showed a bidirectional interference: a positive interference observed at digoxin level <1.8 ng/ml, changing to a negative interference at higher digoxin concentrations. The authors conclude that in countries such as Germany, where both digoxin and Digitoxin may be prescribed, caution should be used to interpret digoxin immunoassay results. Digoxin assays, with cross-reactivity to Digitoxin <0.1% should be used.
-
rapid detection of oleander poisoning using fluorescence polarization immunoassay for Digitoxin effect of treatment with digoxin specific fab antibody fragment ovine
American Journal of Clinical Pathology, 1997Co-Authors: Amitava Dasgupta, Amy P HartAbstract:Poisoning from the oleander plant is common. Taking advantage of the high cross-reactivity of oleandrin, the major cardiac glycoside found in the oleander plant, we demonstrated that the serum Digitoxin assay can be successfully used for the rapid diagnosis of oleander poisoning. Digitoxin is rarely used for treatment of cardiac disorders in the United States and has a therapeutic range of 19.7 to 39.3 nmol/L. In a typical oleander poisoning, serum oleandrin concentrations may reach 174 mmol/L or more. A serum specimen supplemented with 174 mmol/L of oleandrin containing no Digitoxin showed an apparent Digitoxin concentration of 1,272.1 nmol/L, a very high value compared with the range of the serum Digitoxin assay, which is 2.6 to 104.8 nmol/L. Moreover, the response of the serum Digitoxin assay with serum specimens containing various concentrations of oleandrin (and no Digitoxin) is linear. Therefore, the oleandrin concentration in serum can be calculated from the apparent Digitoxin concentration to access the severity of poisoning. Recently, the usefulness of the digoxin-specific Fab antibody fragment in the treatment of oleander poisoning has been described; however, no laboratory test was performed to demonstrate the progress of therapy. We demonstrated that the digoxin-specific Fab antibody can bind oleandrin in vitro, thus reducing the pharmacologically active free oleandrin. Because Fab and oleandrin bound to Fab are absent in the protein-free ultrafiltrates, monitoring the activity of free oleandrin in the ultrafiltrates can be used for monitoring the effectiveness of therapy.
Yon Rojanasakul - One of the best experts on this subject based on the ideXlab platform.
-
monosaccharide Digitoxin derivative sensitize human non small cell lung cancer cells to anoikis through mcl 1 proteasomal degradation
Biochemical Pharmacology, 2014Co-Authors: George A Odoherty, Varisa Pongrakhananon, Todd A Stueckle, Hua Yu Leo Wang, Cerasela Zoica Dinu, Pithi Chanvorachote, Yon RojanasakulAbstract:Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, Digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with Digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than Digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and Digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and Digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
-
Digitoxin and its analogs as novel cancer therapeutics
Experimental Hematology & Oncology, 2012Co-Authors: Hosam A Elbaz, Todd A Stueckle, Yon Rojanasakul, Cerasela Zoica DinuAbstract:A growing body of evidence indicates that Digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of Digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of Digitoxin or synthetic analogs is still subject to study while concerns about Digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on Digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of Digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.
-
stereochemical survey of Digitoxin monosaccharides new anticancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non small cell lung cancer cell
ACS Medicinal Chemistry Letters, 2011Co-Authors: Hua Yu Leo Wang, Todd A Stueckle, Yon Rojanasakul, Maoqua Zhou, George A OdohertyAbstract:A stereochemically diverse array of monosaccharide analogues of the trisaccharide-based cardiac glycoside natural product Digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against nonsmall cell human lung cancer cells (NCI-H460). The results were compared with Digitoxin and its aglycone digitoxigenin. Three novel Digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that Digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar antiproliferation effects but with at least 5-fold greater potency in apoptosis induction than Digitoxin against NCI-H460. This study demonstrates the ability to improve the Digitoxin anticancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.
Todd A Stueckle - One of the best experts on this subject based on the ideXlab platform.
-
monosaccharide Digitoxin derivative sensitize human non small cell lung cancer cells to anoikis through mcl 1 proteasomal degradation
Biochemical Pharmacology, 2014Co-Authors: George A Odoherty, Varisa Pongrakhananon, Todd A Stueckle, Hua Yu Leo Wang, Cerasela Zoica Dinu, Pithi Chanvorachote, Yon RojanasakulAbstract:Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, Digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with Digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than Digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and Digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and Digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
-
Digitoxin and its analogs as novel cancer therapeutics
Experimental Hematology & Oncology, 2012Co-Authors: Hosam A Elbaz, Todd A Stueckle, Yon Rojanasakul, Cerasela Zoica DinuAbstract:A growing body of evidence indicates that Digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of Digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of Digitoxin or synthetic analogs is still subject to study while concerns about Digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on Digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of Digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.
-
stereochemical survey of Digitoxin monosaccharides new anticancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non small cell lung cancer cell
ACS Medicinal Chemistry Letters, 2011Co-Authors: Hua Yu Leo Wang, Todd A Stueckle, Yon Rojanasakul, Maoqua Zhou, George A OdohertyAbstract:A stereochemically diverse array of monosaccharide analogues of the trisaccharide-based cardiac glycoside natural product Digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against nonsmall cell human lung cancer cells (NCI-H460). The results were compared with Digitoxin and its aglycone digitoxigenin. Three novel Digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that Digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar antiproliferation effects but with at least 5-fold greater potency in apoptosis induction than Digitoxin against NCI-H460. This study demonstrates the ability to improve the Digitoxin anticancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.