Publications by authors named "Kavitha Godugu"

20 Publications

  • Page 1 of 1

Anti-Cancer Activities of Thyrointegrin αβ Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma.

Cancers (Basel) 2021 Jun 3;13(11). Epub 2021 Jun 3.

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12208, USA.

Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P-bi-TAT, Compound ) and the removal of one TAT molecule (P-m-TAT, Compound ) versus P-bi-TAT, Compound . The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by >90% at all doses compared to the control (ON Treatment, *** < 0.001) in cells treated with Compounds , , and in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy.
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http://dx.doi.org/10.3390/cancers13112780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199894PMC
June 2021

Discovery of dual targeting PEGylated BG-P-TAT to norepinephrine transporter (NET) and thyrointegrin αvβ3 in the treatment of neuroblastoma.

Bioorg Med Chem 2021 Jun 17;43:116278. Epub 2021 Jun 17.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States. Electronic address:

Polymer-drug conjugates are growing in interest as novel anticancer agents for targeted cancer therapy. The aim of this study was to synthesize a poly(ethylene glycol) (PEG) conjugated anticancer drug for neuroblastoma, which is the most common extracranial solid tumor of childhood and the deadliest tumor of infancy. In our previous studies, we designed and synthesized a dual targeting agent using benzylguanidine (BG) conjugated with the high affinity thyrointegrin αvβ3 antagonist TriAzole Tetraiodothyroacetic acid (TAT) via non-cleavable bonding to PEG400 to make BG-P-TAT and its derivatives as agents against neuroblastoma. Here, we improved the pharmacodynamic properties and increased the solubility by changing the polymer length to 1600 molecular weight. The TAT group, which acts as an integrin αvβ3 antagonist, and the BG group, which can be taken up by neuroblastoma cells through the norepinephrine transporter (NET) system, are conjugated to PEG to make BG-PEG-TAT. The binding affinity of BG-PEG-TAT was 40-fold higher to integrin αvβ3 versus BG-P-TAT and was associated with greater anticancer activities against neuroblastoma cells (SK-N-F1 and SKNAS) implanted in SCID mice along with broad spectrum anti-angiogenesis activities versus the FDA approved anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody Avastin (bevacizumab). In conclusion, our novel dual targeting of NET and αvβ3 receptor antagonist, BG-P1600-TAT demonstrated broad spectrum anti-angiogenesis and anti-cancer activities in suppressing neuroblastoma tumor progression and metastasis. Thus, BG-PEG-TAT represents a potential clinical candidate for targeted therapy in neuroblastoma management.
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http://dx.doi.org/10.1016/j.bmc.2021.116278DOI Listing
June 2021

Thymoquinone and its nanoformulation attenuate colorectal and breast cancers and alleviate doxorubicin-induced cardiotoxicity.

Nanomedicine (Lond) 2021 Jun 16. Epub 2021 Jun 16.

Pharmaceutical Research Institute, Albany College of Pharmacy & Health Sciences, Rensselaer, NY 12144, USA.

To investigate the anti-cancer potential of thymoquinone (TQ) and TQ nanoparticles (TQ-NPs) and their protection against doxorubicin (DOX)-induced cardiotoxicity. TQ-NPs were prepared by double emulsion method and characterized. The efficacy of TQ and TQ-DOX was studied against HCT116 and MDA-MB-231-Luc cancer cell lines and in a xenograft tumor model. TQ and TQ + DOX increased Bax levels in HCT116 cells and decreased Bcl2 levels in MDA-MB-231-Luc cells. In the xenograft model, the TQ-NPs, with an average size of 218 nm, in combination with DOX, significantly reduced tumor size. The combination of TQ or TQ-NPs with DOX significantly reduced DOX-induced cardiotoxicity. Data suggest the promising role of TQ and TQ-NPs alone and with DOX for anti-cancer and cardiac protection benefits.
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http://dx.doi.org/10.2217/nnm-2021-0103DOI Listing
June 2021

Design, synthesis, and biological evaluation of novel bifunctional thyrointegrin antagonists for neuroblastoma.

Bioorg Med Chem 2021 Jul 6;42:116250. Epub 2021 Jun 6.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, United States. Electronic address:

Receptor-mediated cancer therapy has received much attention in the last few decades. Neuroblastoma and other cancers of the sympathetic nervous system highly express norepinephrine transporter (NET) and cell plasma membrane integrin αvβ3. Dual targeting of the NET and integrin αvβ3 receptors using a Drug-Drug Conjugate (DDC) might provide effective treatment strategy in the fight against neuroblastoma and other neuroendocrine tumors. In this work, we synthesized three dual-targeting BG-P-TAT derivatives, dI-BG-P-TAT, dM-BG-P-TAT, and BG-P-PAT containing di-iodobenzene, di-methoxybenzene, and piperazine groups, respectively. These derivatives utilize to norepinephrine transporter (NET) and the integrin αvβ3 receptor to simultaneously modulate both targets based on evaluation in a neuroblastoma animal model using the neuroblastoma SK-N-F1 cell line. Among the three synthesized agents, the piperazine substituted BG-P-PAT exhibited potent integrin αvβ3 antagonism and reduced neuroblastoma tumor growth and cancer cell viability by >90%. In conclusion, BG-P-PAT and derivatives represent a potential therapeutic approach in the management of neuroblastoma.
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http://dx.doi.org/10.1016/j.bmc.2021.116250DOI Listing
July 2021

Nano Diaminopropane tetrac and integrin αvβ3 expression in different cancer types: Anti-cancer efficacy and Safety.

Cancer Treat Res Commun 2021 May 13;28:100395. Epub 2021 May 13.

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, , 1 Discovery Drive, Rensselaer, NY, USA. Electronic address:

Integrins are a family of heterodimeric plasma membrane glycoproteins, which regulate tumor growth, angiogenesis, migration, and metastasis. Integrin αvβ3 has been recognized as a putative target for the treatment of several cancers. Thus, the characterization of αvβ3 distribution in different human tumors is of substantial interest in tumor targeting and its suppression. In this study we evaluated the expression of integrin αvβ3 in different cancer types to define the expression pattern in cancer model. Furthermore, we investigated the effect of novel αvβ3 antagonist Diaminopropane Tetraiodothyroacetic acid conjugated to poly (lactic-co-glycolic acid) polymer and its nanoformulated form (NDAT), on different cancer cell lines both in vitro and in xenografts. In vitro, NDAT downregulated αv and β3 monomer expression. In vivo in tumor xenografts, similarly, NDAT downregulated αv and β3. Distinct reduction in tumor weight and viability was observed in glioblastoma xenografts treated with NDAT. Furthermore, NDAT was safe and tolerable in mice treated with high doses. In conclusion, NDAT is an effective and safe inhibitor of integrin αvβ3 expression in various cancer types, which indicates its impact on the targetability and suppression of αvβ3-associated tumor functions.
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http://dx.doi.org/10.1016/j.ctarc.2021.100395DOI Listing
May 2021

New Thyrointegrin αβ Antagonist with a Scalable Synthesis, Brain Penetration, and Potent Activity against Glioblastoma Multiforme.

J Med Chem 2021 05 22;64(9):6300-6309. Epub 2021 Apr 22.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive (Room 238), Rensselaer 12144, New York, United States.

We have previously reported that the αβ inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanalysis problems due to PEG polydispersity and large-scale synthesis issues led to a search for new molecules, culminating in the discovery of fb-PMT, a conjugate of tetrac and monodisperse PEG36, with a lipophilic 4-fluorobenzyl group at the opposite end of the PEG chain. fb-PMT reduces GBM tumor growth and viability by up to 98%, is suitable for large-scale synthesis, and is amenable to bioanalysis using mass spectrometry-based detection. We also showed that changes in lipophilicity at the opposite end of the PEG chain from the active tetrac component affected the proton NMR chemical shift of the tetrac moiety in D0 and brain levels of the compound after subcutaneous dosing.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00350DOI Listing
May 2021

Sulfated non-anticoagulant low molecular weight heparin in the prevention of cancer and non-cancer associated thrombosis without compromising hemostasis.

Thromb Res 2021 04 26;200:109-114. Epub 2021 Jan 26.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA. Electronic address:

Introduction: Cancer-associated thrombosis (CAT) accounts for about 20% of all cases of Venous Thromboembolism (VTE). Tissue factor (TF) is documented to be highly expressed on cancer cells and pathological angiogenic endothelial cells. Here, we used a novel oxidized sulfated ultra-LMWH, S-NACH, which is devoid of anti-factor Xa and IIa activities with limited to no systemic anticoagulant effects. This sulfated form has enhanced binding to vascular endothelial cells (EC) and releases and potentiates the action of tissue factor pathway inhibitor (TFPI). S-NACH binds with high affinity to EC, releases and binds to EC TFPI, and promotes vascular antithrombotic effect with limited to no risk of bleeding complications.

Materials And Methods: We investigated the effects of S-NACH on clot kinetics in vitro and in vivo. Also, we investigated the effects of S-NACH on CAT mediated by human acute leukemia cells (K562) and human pancreatic cancer cells (SUIT2).

Results: S-NACH was associated with ~3-fold increase of TFPI 2 levels within 3 h. Also, S-NACH reversed the hypercoagulability state that is associated with cancer cells in vitro. In vivo, S-NACH at 20 mg/kg subcutaneously (SC) had no effect on bleeding time compared to both tinzaparin and enoxaparin at 5 mg/kg SC. S-NACH did not show any anti-IIa or anti-Xa activities in comparison to tinzaparin and enoxaparin (p < 0.001).

Conclusion: Data suggest the importance of S-NACH through its EC binding, EC TFPI release and its interaction with TFPI in enhancing its activity in the prevention of cancer and non-cancer associated thrombosis with limited to no bleeding complications.
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http://dx.doi.org/10.1016/j.thromres.2021.01.015DOI Listing
April 2021

The effects of aspirin and N-3 fatty acids on telomerase activity in adults with diabetes mellitus.

Nutr Metab Cardiovasc Dis 2020 09 25;30(10):1795-1799. Epub 2020 Jun 25.

Department of Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address:

Type 2 Diabetes mellitus is associated with aging and shortened telomere length. Telomerase replaces lost telomeric repeats at the ends of chromosomes and is necessary for the replicative immortality of cells. Aspirin and the n3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are commonly used therapies in people with type 2 diabetes for reducing cardiovascular disease events, though their relation to telomerase activity is not well studied. We explored the effects of aspirin, EPA + DHA, and the combined effects of aspirin and EPA + DHA treatment on telomerase activity in 30 adults with diabetes mellitus. EPA and DHA ingestion alone increased telomerase activity then a decrease occurred with the addition of aspirin consumption. Crude (F-stat = 2.09, p = 0.13) and adjusted (F-stat = 2.20, p = 0.14) analyses of this decrease showed signs of a trend. These results suggest that aspirin has an adverse effect on aging in diabetics who have relatively high EPA and DHA ingestion.
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http://dx.doi.org/10.1016/j.numecd.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494550PMC
September 2020

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma.

J Med Chem 2020 07 7;63(14):7653-7662. Epub 2020 Jul 7.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive (Room 238), Rensselaer, New York 12144, United States.

Therapeutic targeting of the norepinephrine transporter (NET) function with benzylguanidine (BG), conjugated with the high-affinity thyrointegrin αvβ3 antagonist triazole tetraiodothyroacetic acid, TAT, via noncleavable bonding to poly(ethylene glycol) (PEG) (P) might allow for effective treatment options in neuroblastoma. BG-P-TAT is a dual-targeting agent, targeting the NET function and the thyrointegrin αvβ3 receptors that are overexpressed in neuroblastoma and other neuroendocrine tumors. Various cancer cells and actively dividing tumor-endothelial cells express the thyrointegrin αvβ3 receptors. In this work, the novel compound BG-P-TAT was synthesized and evaluated in the neuroblastoma SK-N-FI cell line for improved targeting and to offer a new strategy for patients with neuroblastoma. BG-P-TAT demonstrated significant suppression of neuroblastoma tumor progression, growth, and viability in a dose-dependent manner. In conclusion, BG-P-TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00537DOI Listing
July 2020

Nanoformulated Ajwa (Phoenix Dactylifera) Bioactive Compounds Improve the Safety of Doxorubicin without Compromising its Anticancer Efficacy in Breast Cancer.

Molecules 2020 Jun 3;25(11). Epub 2020 Jun 3.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.

One of the major causes of women's death in the world is breast cancer. Consequently, numerous regimens for the control of this severe disease have been created. The chemotherapeutic agent doxorubicin (DOX) is frequently used to treat breast cancer, but DOX can also cause cardiotoxic effects that lead to heart failure. Therefore, many research studies have been done to find a natural product that effectively potentiates or does not interfere with DOX's anticancer effect and protects against its cardiotoxicity. We studied the impact of combined nanoformulated Ajwa (Phoenix dactylifera) selected bioactive compounds (BAC) rutin (R) and quercetin (Q) in nude mice breast cancer xenografts on DOX-mediated anticancer efficacy. We also studied if this Ajwa BAC could safeguard against DOX-mediated cardiomyopathies by evaluating plasma cardiac troponin-I (cTn-I) levels and cardiac histopathology. Nanoformulated Ajwa BAC effectively alleviated weight loss induced by DOX in mice and significantly decreased the elevated cTn-I. Furthermore, 5 mg RQ-NPs/kg of nude mice that subcutaneously daily injected for 11 days, attenuated the histopathological alterations induced in cardiac muscles due to DOX without any interference with the anticancer effects of DOX against breast cancer.
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http://dx.doi.org/10.3390/molecules25112597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321378PMC
June 2020

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin αβ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme.

Bioconjug Chem 2019 12 25;30(12):3087-3097. Epub 2019 Nov 25.

Pharmaceutical Research Institute , Albany College of Pharmacy and Health Sciences , Rensselaer , New York 12144 , United States.

Discovery of bioactive molecules that target integrins has implicated their role in tumor angiogenesis, tumor growth, metastasis, and other pathological angiogenesis processes. Integrins are members of a family of cell surface receptors that play a critical role in the angiogenesis process. Tetraiodothyroacetic acid (tetrac), a deaminated derivative of l-thyroxine (T4), is a "thyrointegrin" antagonist that blocks the actions of l-triiodothyronine (T3) and T4 with an interaction site that is located at or near the RGD recognition site identified on integrin αβ's binding pocket (thyrointegrin αβ receptors). We have enhanced the biological activity of a tetrac-based inhibitor via significantly improving its αβ receptor binding affinity by introducing a triazole ring on the outer ring of tetrac and covalently conjugating to polymer to increase the product's hydrophilicity via PEGylation. The product, P-bi-TAT, was restricted from nuclear translocation and demonstrated high blood brain barrier permeability and retention in contrast to the non-PEG conjugated derivative. Results of biological activity indicated that this macromolecule new chemical entity P-bi-TAT has greater than 400-fold potent integrin αβ affinity versus the parent compound tetrac and has potent anticancer/anti-angiogenesis efficacy against glioblastoma multiforme (GBM). P-bi-TAT administered subcutaneously once daily for 21 days at 1-10 mg/kg mouse body weight resulted in a dose-dependent suppression of GBM tumor growth and viability as monitored with IVIS imaging ( < 0.001). GBM tumors had >95% volume loss and maximal loss of GBM cell viability during the 21 days ON-treatment experiment as well as in the 21 days ON followed by 21 days OFF-treatment experiment ( < 0.001). In conclusion, P-bi-TAT is a promising lead clinical candidate effective in the treatment of human GBM.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00742DOI Listing
December 2019

Pharmacokinetics, Biodistribution, and Anti-Angiogenesis Efficacy of Diamino Propane Tetraiodothyroacetic Acid-conjugated Biodegradable Polymeric Nanoparticle.

Sci Rep 2019 06 21;9(1):9006. Epub 2019 Jun 21.

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.

The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin αvβ3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin αvβ3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug concentration curve AUC by 4-fold at a dose of 3 mg/kg when compared with DAT, and C of NDAT (4363 ng/mL) was 8-fold greater than that of DAT (548 ng/mL). Biodistribution studies in the mice showed that the concentrations of NDAT were higher than DAT/Cremophor EL micelles in heart, lung, liver, spleen, and kidney. In another mouse model using female NCr nude homozygous mice with U87 xenografts, tumor growth was significantly decreased at doses of 1 and 3 mg/kg of NDAT. In the chick chorioallantoic membrane (CAM) assay used to measure angiogenesis, DAT (500 ng/CAM) resulted in 48% inhibition of angiogenesis levels. In comparison, NDAT at low dose (50 ng/CAM) showed 45% inhibition of angiogenesis levels. Our investigation of NDAT bridges the study of polymeric nanoparticles and anti-angiogenic agents and offers new insight for the rational design of anti-angiogenic agents.
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http://dx.doi.org/10.1038/s41598-019-44979-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588584PMC
June 2019

Novel Targeted Nano-Parthenolide Molecule against NF-kB in Acute Myeloid Leukemia.

Molecules 2019 Jun 3;24(11). Epub 2019 Jun 3.

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.

The targeted nano-encapsulation of anticancer drugs can improve drug delivery and the selective targeting of cancer cells. Nuclear factor kappa B (NF-kB) is a regulator for different biological responses, including cell proliferation and differentiation. In acute myeloid leukemia (AML), constitutive NF-κB has been detected in more than 50% of cases, enabling leukemic cells to resist apoptosis and stimulate uncontrolled proliferation. We evaluated NF-kB expression in bone marrow samples from 103 patients with AML using quantitative real time polymerase chain reaction (RT-PCR) and found that expression was increased in 80.5% (83 out 103) of these patients with AML in comparison to the control group. Furthermore, overexpressed transmembrane glycoprotein (CD44) on leukemic cells in comparison to normal cells is known to play an important role in leukemic cell engraftment and survival. We designed poly lactide co-glycolide (PLGA) nanoparticles conjugated with antiCD44 and encapsulating parthenolide (PTL), a nuclear factor kappa B (NF-kB) inhibitor, in order to improve the selectivity and targeting of leukemic cells and to spare normal cells. In vitro, in leukemic cell lines Kasumi-1, KG-1a, and THP-1, proliferation was decreased by 40% (** < 0.01) with 5 µM PLGA-antiCD44-PTL nanoparticles in comparison to the same concentration of free PTL (~10%). The higher uptake of the nanoparticles by leukemic cells was confirmed with confocal microscopy. In conclusion, PLGA-antiCD44-PTL nanoparticles improved the bioavailability and selective targeting of leukemic cells, thus holding promise as a drug delivery system to improve the cure rate of AML.
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http://dx.doi.org/10.3390/molecules24112103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600366PMC
June 2019

Fluorinated Analog NMR s of Organosulfur Compounds from Garlic (Allium sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies.

Molecules 2017 Nov 28;22(12). Epub 2017 Nov 28.

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.

We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and -2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((,)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition ( < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested.
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http://dx.doi.org/10.3390/molecules22122081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149718PMC
November 2017

Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1.

Oncotarget 2016 Sep;7(36):57811-57820

The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.

Acute myeloid leukemia (AML) patients show high relapse rates and some develop conventional chemotherapy resistance. Leukemia Stem Cells (LSCs) are the main player for AML relapses and drug resistance. LSCs might rely on the B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) in promoting cellular proliferation and survival. Growth of LSCs in microenvironments that are deprived of nutrients leads to up-regulation of the signaling pathways during the progression of the disease, which may illustrate the sensitivity of LSCs to inhibitors of those signaling pathways as compared to normal cells. We analyzed the expression of LSC markers (CD34, CLL-1, TIM-3 and BMI-1) using quantitative RT-PCR in bone marrow samples of 40 AML patients of different FAB types (M1, M2, M3, M4, M5, and M7). We also studied the expression of these markers in 2 AML cell lines (Kasumi-1 and KG-1a) using flow cytometry and quantitative RT-PCR. The overexpression of TIM-3, CLL-1, and BMI-1 was markedly correlated with poor prognosis in these patients. Our in vitro findings demonstrate that targeting BMI-1, which markedly increased in the leukemic cells, was associated with marked decrease in leukemic burden. This study also presents results for blocking LSCs' surface markers CD44, CLL-1, and TIM-3. These markers may play an important role in elimination of AML. Our study indicates a correlation between the expression of markers TIM-3, CLL-1, and especially of BMI-1 and the aggressiveness of AML and thus the potential impact of prognosis and therapies that target LSCs on improving the cure rates.
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http://dx.doi.org/10.18632/oncotarget.11063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295391PMC
September 2016

Gender differences in alcohol-induced oxidative stress and altered membrane properties in erythrocytes of rats.

Indian J Biochem Biophys 2013 Feb;50(1):32-9

Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515055, Andhra Pradesh, India.

Alcohol-induced oxidative stress leads to imbalance between reactive oxygen species (ROS) and the antioxidant defense system, resulting in oxidative damage to membrane components such as lipids and proteins, ultimately altering membrane properties. In this study, we assessed oxidative stress status and alterations in erythrocyte membrane properties in alcohol-administered rats with respect to gender difference. Alcohol (20% v/v) administered rats of both genders showed significant changes in plasma lipid profile with elevated nitrite/nitrate levels. Furthermore, alcohol-administration significantly decreased erythrocyte antioxidant enzymes and enhanced erythrocyte membrane lipid peroxidation, cholesterol/phospholipid (C/P) ratio and Na+/K(+)-ATPase activity in both males and females. Besides, anisotropic studies revealed that alcohol-administration significantly decreased erythrocyte membrane fluidity. In conclusion, alcohol-administration significantly increased oxidative stress by decreasing antioxidant status, and subsequent generation of ROS altered membrane properties by altering fluidity and Na+/K(+)-ATPase activity. Female rats were more vulnerable to alcohol-induced biochemical and biophysical changes in plasma and erythrocyte including oxidative stress than male rats.
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February 2013

Alcohol-induced oxidative/nitrosative stress alters brain mitochondrial membrane properties.

Mol Cell Biochem 2013 Mar 1;375(1-2):39-47. Epub 2012 Dec 1.

Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515 055, AP, India.

Chronic alcohol consumption causes numerous biochemical and biophysical changes in the central nervous system, in which mitochondria is the primary organelle affected. In the present study, we hypothesized that alcohol alters the mitochondrial membrane properties and leads to mitochondrial dysfunction via mitochondrial reactive oxygen species (mROS) and reactive nitrogen species (RNS). Alcohol-induced hypoxia further enhances these effects. Administration of alcohol to rats significantly increased the mitochondrial lipid peroxidation and protein oxidation with decreased SOD2 mRNA and protein expression was decreased, while nitric oxide (NO) levels and expression of iNOS and nNOS in brain cortex were increased. In addition, alcohol augmented HIF-1α mRNA and protein expression in the brain cortex. Results from this study showed that alcohol administration to rats decreased mitochondrial complex I, III, IV activities, Na(+)/K(+)-ATPase activity and cardiolipin content with increased anisotropic value. Cardiolipin regulates numerous enzyme activities, especially those related to oxidative phosphorylation and coupled respiration. In the present study, decreased cardiolipin could be ascribed to ROS/RNS-induced damage. In conclusion, alcohol-induced ROS/RNS is responsible for the altered mitochondrial membrane properties, and alcohol-induced hypoxia further enhance these alterations, which ultimately leads to mitochondrial dysfunction.
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http://dx.doi.org/10.1007/s11010-012-1526-1DOI Listing
March 2013

Emblica officinalis ameliorates alcohol-induced brain mitochondrial dysfunction in rats.

J Med Food 2011 Jan-Feb;14(1-2):62-8. Epub 2010 Dec 7.

Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, AP, India.

The fruit of Emblica officinalis has been used in the Ayurvedic system of medicine for the treatment of different ailments and is also an ingredient of various traditional medicinal herbal formulations in India and other countries. To investigate the protective effect of Emblica officinalis fruit extract (EFE) against alcohol-induced brain mitochondrial dysfunction, male Wistar rats were orally administered 20% alcohol (5 g/kg of body weight/day) and EFE (250 mg/kg of body weight/day) for 60 days. Alcohol-treated rats showed significantly lowered activities of mitochondrial antioxidant enzymes (superoxide dismutase and glutathione peroxidase) and reduced glutathione compared with those of experimental control rats. Furthermore, alcohol feeding lowered the activities of NADH dehydrogenase, succinate dehydrogenase (SDH), and cytochrome c oxidase and the content of cytochromes followed by increased levels of nitric oxide (NO), thiobarbituric acid-reactive substances, and protein carbonyls. No significant change was observed in membrane potential. Administration of EFE to alcohol-treated rats, lowered the levels of NO, protein carbonyls, and lipid peroxidation and elevated the activities of the antioxidant enzymes SDH, NADH dehydrogenase, and cytochrome c oxidase and the content of cytochromes. The active tannoid principles present in EFE with its antioxidant as well as NO scavenging properties might have contributed to the observed protection against alcohol-induced brain mitochondrial dysfunction.
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http://dx.doi.org/10.1089/jmf.2010.1122DOI Listing
May 2011

Chronic cigarette smoking alters erythrocyte membrane lipid composition and properties in male human volunteers.

Nitric Oxide 2010 Nov 31;23(3):181-6. Epub 2010 May 31.

Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, AP 515055, India.

Cigarette smoking is a major lifestyle factor influencing the health of human beings. The present study investigates smoking induced alterations on the erythrocyte membrane lipid composition, fluidity and the role of nitric oxide. Thirty experimental and control subjects (age 35+/-8) were selected for the study. Experimental subjects smoke 12+/-2 cigarettes per day for 7-10 years. In smokers elevated nitrite/nitrate levels in plasma and red cell lysates were observed. Smokers showed increased hemolysis, erythrocyte membrane lipid peroxidation, protein carbonyls, C/P ratio (cholesterol and phospholipid ratio), anisotropic (gamma) value with decreased Na(+)/K(+)-ATPase activity and sulfhydryl groups. Alterations in smokers erythrocyte membrane individual phospholipids were also evident from the study. Red cell lysate nitric oxide positively correlated with C/P ratio (r=0.565) and fluorescent anisotropic (gamma) value (r=0.386) in smokers. Smoking induced generation of reactive oxygen/nitrogen species might have altered erythrocyte membrane physico-chemical properties.
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http://dx.doi.org/10.1016/j.niox.2010.05.287DOI Listing
November 2010