Browsing by Author "Sudha, Thangirala"
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Item Alpha v beta 3 integrin antagonists enhance chemotherapy response in an orthotopic pancreatic cancer model(Frontiers Media, 2020-01-27) Sudha, Thangirala; Bharali, Dhruba J.; Davis, Paul J.; Mousa, Shaker A.; Coşkun, Melis Debreli; Çelikler, Serap; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-4177-3478; CML-2517-2022; 57194630463; 8234554800Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether alpha v beta 3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1 beta, IL-6, IL-10, and TNF-alpha from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kappa B may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.Publication Lead-induced endothelial cell dysfunction: Protective effect of sulfated non-anticoagulant low molecular weight heparin(Korean Soc Environmental Risk Assessment & Health Science, 2021-04-12) Motawei, Shimaa M.; Sudha, Thangirala; Godugu, Kavitha; Mousa, Shaker A.; Yalçın, Murat; YALÇIN, MURAT; Bursa Uludağ Üniversitesi/Veteriner Fakültesi.; 0000-0002-5600-8162; AAG-6956-2021Objective The aim of this investigation is to determine the potential protective effect and mechanism of a novel non-anticoagulant heparin-derived product on lead (Pb) mediated endothelial cells (ECs) toxicity. Pb is known to have detrimental effects on human health by affecting the function of all systems of the human body due to its toxicity on ECs. Altered activities of the protective substances secreted by the vascular endothelium such as EC's tissue factor pathway inhibiter (TFPI), nitric oxide and other protective factors might increase the risk for vascular disorders. Heparin and its sulfated non-anticoagulant low molecular weight heparin (S-NACH) are known to enhance TFPI release from ECs, which is a protective mechanism for the ECs against thrombo-inflammation. Methods We examined 3-100 mu M Pb-induced dysfunction on ECs and the potential protective effect of 1-10 mu M S-NACH in returning the ECs' normal function. Methods included an in vitro tube formation assay and an in vivo Matrigel plug angiogenesis model in mice. Results We found that Pb-induced EC dysfunction by inhibiting EC viability. The cytotoxic effect of 3-100 mu M Pb on ECs inhibited angiogenesis in a dose-dependent manner. Pb disrupted ECs' normal physiological function by hindering the release of its endogenous vascular protective mediators TFPI-1 and TFPI-2. The impairment effect of 3-30 mu M Pb on ECs' release of both TFPIs was effectively reversed to normal levels by S-NACH in a concentration-dependent manner and combatted the harmful Pb effects on physiological angiogenesis. Conclusions Our data indicate that S-NACH, which is devoid of bleeding side effects, can effectively reverse potentially high-risk Pb-mediated endothelial cytotoxicity by reversing the physiological release of endogenous EC TFPIs.Publication Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis(Dove Medical Press Ltd, 2014-01-01) Davis, Paul J.; Lin, Hung-Yun; Sudha, Thangirala; Yalçın, Murat; Tang, Heng-Yuan; Hercbergs, Aleck; Leith, John T.; Luidens, Mary K.; Ashur-Fabian, Osnat; Incerpi, Sandra; Mousa, Shaker A.; YALÇIN, MURAT; Uludağ Üniversitesi/Tıp Fakültesi/Radyasyon Onkolojisi Anabilim Dalı; 0000-0002-5600-8162; AAG-6956-2021The extracellular domain of integrin alpha v beta 3 contains a receptor for thyroid hormone and hormone analogs. The integrin is amply expressed by tumor cells and dividing blood vessel cells. The proangiogenic properties of thyroid hormone and the capacity of the hormone to promote cancer cell proliferation are functions regulated nongenomically by the hormone receptor on alpha v beta 3. An L-thyroxine (T-4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T-4 and 3,5,3'-triiodo-L-thyronine (T-3) by alpha v beta 3 and inhibits angiogenic activity of thyroid hormone. Covalently bound to a 200 nm nanoparticle that limits its activity to the cell exterior, tetrac reformulated as Nanotetrac has additional effects mediated by alpha v beta 3 beyond the inhibition of binding of T-4 and T-3 to the integrin. These actions of Nanotetrac include disruption of transcription of cell survival pathway genes, promotion of apoptosis by multiple mechanisms, and interruption of repair of double-strand deoxyribonucleic acid breaks caused by irradiation of cells. Among the genes whose expression is suppressed by Nanotetrac are EGFR, VEGFA, multiple cyclins, catenins, and multiple cytokines. Nanotetrac has been effective as a chemotherapeutic agent in preclinical studies of human cancer xenografts. The low concentrations of alpha v beta 3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies.Item OT-404, multi-targeted anti-cancer agent affecting tumor proliferation, chemo-resistance, and angiogenesis(Elsevier, 2013-05) Rebbaa, Abdelhadi; Patil, Ghanshyam; Sudha, Thangirala; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Veteriner Hekimliği Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734There is a need for a comprehensive anti-cancer strategy that simultaneously targets abnormal proliferation, angiogenesis rates, and development of chemotherapy resistance. We have identified a small molecule, OT-404, that effectively inhibited proliferation and angiogenesis of either chemo-sensitive or resistant human cancer cells and enhanced cancer cell sensitivity to different chemotherapy. In vivo studies of human tumor xenografts in nude mice showed that OT-404, used alone or encapsulated into nanoparticles, inhibited the growth of doxorubicin-resistant breast cancer MCF-7 by more than 80%, and by 95% when combined with doxorubicin. These findings provide evidence for the potential of OT-404 in cancer management.Item Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles(Springer, 2013-06) Lin, Hungyung; Sudha, Thangirala; Bharali, Dhruba Jyoti; Meng, Ran; Tang, Hengyuan; Davis, Faith B.; Stain, Steven Charles; Davis, Paul J.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caused accumulation of pro-apoptotic protein BcLx-s. Tetrac NP was more effective than tetrac in increasing cellular abundance of mRNAs of pro-apoptotic p53 and p21 and anti-angiogenesis thrombospondin 1 protein in PANC-1 and MPanc96 cancer cell lines. Tetrac NP noticeably decreased expression of EGFR and of anti-apoptosis gene XIAP; tetrac did not affect EGFR and increased XIAP mRNA in both MPanc96 and PANC-1. In conclusion, tetrac or Tetrac NP effectively inhibited human pancreatic xenograft growth and tumor angiogenesis via a plasma membrane receptor that downstream modulated cellular abundance of proteins or mRNAs relevant to apoptosis and angiogenesis.Item Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin(Elsevier Ireland, 2014-08-01) Sudha, Thangirala; Lin, Thangirala; Elmetwally, Ahmed M.; Nazeer, Tipu; Arumugam, Thiruvengadam; Phillips, Patricia G.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Sulfated non-anticoagulant heparins (S-NACHs) might be preferred for potential clinical use in cancer patients without affecting hemostasis as compared to low molecular weight heparins (LMWHs). We investigated anti-tumor effects, anti-angiogenesis effects, and mechanisms of S-NACH in a mouse model of pancreatic cancer as compared to the LMWH tinzaparin. S-NACH or tinzaparin with or without gemcitabine were administered, and tumor luminescent signal intensity, tumor weight, and histopathology were assessed at the termination of the study. S-NACH and LMWH efficiently inhibited tumor growth and metastasis, without any observed bleeding events with S-NACH as compared to tinzaparin. S-NACH distinctly increased tumor necrosis and enhanced gemcitabine response in the mouse pancreatic cancer models. These data suggest the potential implication of S-NACH as a neoadjuvant in pancreatic cancer.Item Targeted delivery of cisplatin to tumor xenografts via the nanoparticle component of nano-diamino-tetrac(Future Medicine, 2017-02) Sudha, Thangirala; Bharali, Dhruba J; Darwish, Noureldien H.E.; Keating, Kelly A; Lin, Hung-Yun; Davis, Paul J.; Mousa, Shaker A; Yalçın, Murat; Coşkun, Melis Debreli; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; AAF-3992-2020; 57192959734; 57193066146Aim: Nano-diamino-tetrac (NDAT) targets a receptor on integrin alpha v beta 3; alpha v beta 3 is generously expressed by cancer cells and dividing endothelial cells and to a small extent by nonmalignant cells. The tetrac (tetraiodothyroacetic acid) of NDAT is covalently bound to a poly(lactic-co-glycolic acid) nanoparticle that encapsulates anticancer drugs. We report NDAT delivery efficiency of cisplatin to agent-susceptible urinary bladder cancer xenografts. Materials & methods: Cisplatin-loaded NDAT (NDAT-cisplatin) was administered to xenograft-bearing nude mice. Tumor size response and drug content were measured. Results: Intratumoral drug concentration was up to fivefold higher (p < 0.001) in NDAT-cisplatin-exposed lesions than with conventional systemic administration. Tumor volume reduction achieved was NDAT-cisplatin > NDAT without cisplatin > cisplatin alone. Conclusion: NDAT markedly enhances cisplatin delivery to urinary bladder cancer xenografts and increases drug efficacy.Item Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac(Dove Medical, 2017) Sudha, Thangirala; Bharali, Dhruba J.; Darwish, Noureldien H. E.; Keating, Kelly A.; Lin, Hung-Yun; Davis, Paul J.; Mousa, Shaker A. Shaker A.; Yalçın, Murat; Coşkun, Melis Debreli; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; AAF-3992-2020; 57192959734; 57193066146The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin alpha v beta 3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P < 0.001) and 2.3-fold (doxorubicin; P < 0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.