scholarly journals Co-delivery of doxorubicin and conferone by novel pH-responsive β-cyclodextrin grafted micelles triggers apoptosis of metastatic human breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Akram Rahmani ◽  
Fariborz Rahimi ◽  
Mehrdad Iranshahi ◽  
Houman Kahroba ◽  
Amir Zarebkohan ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Annexin V ◽  
The Novel ◽  
Human Breast ◽  
Rt Pcr ◽  
Intrinsic Pathway ◽  
Tumor Cell Apoptosis ◽  
Cell Internalization ◽  
New Perspective ◽  
Induced Apoptosis

AbstractAdjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study, Conferone (Conf) was used as an adjuvant in combination with Doxorubicin (Dox) for inducing apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from the novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100% at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100% for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI < 1). According to cell cycle and Annexin-V apoptosis analysis, Dox-Conf loaded micelle significantly induce tumor cell apoptosis (more than 98% of cells population showed apoptosis at IC50 = 0.259 μg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded βCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicine for combination chemo-adjuvant therapy against malignant cancer.

scholarly journals Co-Delivery of Doxorubicin and Conferone by Novel pH-Responsive β-Cyclodextrin Grafted Micelles Triggers Apoptosis of Metastatic Human Breast Cancer Cells

2021 ◽  
Author(s):  
Akram Rahmani ◽  
Fariborz Rahimi ◽  
Mehrdad Iranshahi ◽  
Houman Kahroba ◽  
Amir Zarebkohan ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Annexin V ◽  
The Novel ◽  
Human Breast ◽  
Rt Pcr ◽  
Intrinsic Pathway ◽  
Tumor Cell Apoptosis ◽  
Cell Internalization ◽  
New Perspective ◽  
Induced Apoptosis

Abstract Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study Conferone (Conf) was used as adjuvant in combination with Doxorubicin (Dox) for induction of apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic β-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 μg/mL, and cell internalization of around 100 % at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100 % for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI<1). According to cell cycle and Annexin-V apoptosis analysis, Dox-Conf loaded micelle significantly induce tumor cell apoptosis (more than 98 % of cells population showed apoptosis at IC50 = 0.259 μg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded βCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicines for combination chemo-adjuvant therapy against malignant cancer.

Induction of RKIP and Inhibition of the Transcription Repressor YY1 in B-NHL by the Novel Proteasome Inhibitor NPI-0052 and Sensitization to TRAIL-Induced Apoptosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2391-2391
Author(s):  
Eriko Suzuki ◽  
Sara Huerta-Yepez ◽  
Stavroula Baritaki ◽  
Michael Palladino ◽  
Benjamin Bonavida
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cells ◽  
Proteasome Inhibitor ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Annexin V ◽  
Underlying Mechanism ◽  
Significant Inhibition ◽  
The Novel ◽  
Induced Apoptosis

Abstract Proteasome inhibitors have been shown to exert multiple effects including direct cytotoxic activity in sensitive cancer cells. In addition, proteasome inhibitors have recently been used therapeutically for certain cancers such as multiple myeloma and mantle cell lymphoma. We have recently reported that the novel proteasome inhibitor, NPI-0052 (Nereus Pharmaceuticals), can sensitize drug-resistant B-NHL tumor cells to apoptosis by various chemotherapeutic drugs. Also, NPI-0052 inhibits the NF-κB survival pathway and inhibition of NF-κB sensitizes tumor cells to TRAIL-induced apoptosis. We hypothesized that inhibition of NF-κB by NPI-0052 may also lead to sensitization of TRAIL-resistant B-NHL cells to TRAIL-mediated apoptosis. Human Burkitt’s lymphoma,Ramos cells, were treated with various concentrations of NPI-0052 (0–10ng/ml for 24h) and were then treated with recombinant human TRAIL (0–100ng/ml for 24h). The cells were examined for apoptosis by Annexin V/PI. The combination treatment resulted in significant potentiation of cytotoxicity and synergy in apoptosis was achieved. We have then examined a potential underlying mechanism of NPI-0052-mediated sensitization. The transcription repressor YY1 was recently shown to negatively regulate the transcription of the TRAIL death receptor DR5 and thus overexpression of YY1 is a resistant factor for TRAIL-induced apoptosis. Hence, treatment of Ramos cells with NPI-0052 resulted in significant inhibition of YY1 expression and upregulation of surface DR5 expression. We have also examined the effect of NPI-0052 on RKIP (Raf-kinase inhibitor protein) (Yeung et al., Molecular Cellular Biology; 21:7207, 2001) expression. Since both NPI-0052 and RKIP inhibit the NF-κB pathway, we hypothesized that treatment of Ramos cells with NPI-0052 may result in significant upregulation of RKIP expression. The findings, indeed, demonstrate that NPI-0052 significantly induced RKIP expression in Ramos cells. Overall, the findings show, for the first time, that NPI-0052 sensitizes B-NHL tumor cells to TRAIL-mediated apoptosis. Sensitization by NPI-0052 was correlated with both the induction of RKIP expression and inhibition of YY1 and upregulation of DR5 expression. Currently, TRAIL or agonist monoclonal antibodies against DR4 or DR5 are being examined clinically for anti-tumor activity. Therefore, our findings suggest the potential application of the combination of NPI-0052 and TRAIL or agonistic monoclonal antibodies against DR4 or DR5 in the treatment of tumor cells that are resistant to drugs and TRAIL.

scholarly journals Role of Na+/Ca2+ Exchangers in Therapy Resistance of Medulloblastoma Cells

2017 ◽  
Vol 42 (3) ◽  
pp. 1240-1251 ◽  
Author(s):  
Lisann Pelzl ◽  
Zohreh Hosseinzadeh ◽  
Tamer al-Maghout ◽  
Yogesh Singh ◽  
Itishri Sahu ◽  
...  
Keyword(s):  
Annexin V ◽  
Therapy Resistance ◽  
Transport Processes ◽  
Protein Abundance ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Cell Current ◽  
Radiation Induced ◽  
Induced Apoptosis

Background/Aims: Alterations of cytosolic Ca2+-activity ([Ca2+]i) are decisive in the regulation of tumor cell proliferation, migration and survival. Transport processes participating in the regulation of [Ca2+]i include Ca2+ extrusion through K+-independent (NCX) and/or K+-dependent (NCKX) Na+/Ca2+-exchangers. The present study thus explored whether medulloblastoma cells express Na+/Ca2+-exchangers, whether expression differs between therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells, and whether Na+/Ca2+-exchangers participate in the regulation of cell survival. Methods: In therapy sensitive D283 and therapy resistant UW228-3 medulloblastoma cells transcript levels were estimated by RT-PCR, protein abundance by Western blotting, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, Na+/ Ca2+-exchanger activity from the increase of [Ca2+]i (Δ[Ca2+]i) and from whole cell current (Ica) following abrupt replacement of Na+ containing (130 mM) and Ca2+ free by Na+ free and Ca2+ containing (2 mM) extracellular perfusate as well as cell death from PI -staining and annexin-V binding in flow cytometry. Results: The transcript levels of NCX3, NCKX2, and NCKX5, protein abundance of NCX3, slope and peak of Δ[Ca2+]i as well as Ica were significantly lower in therapy sensitive D283 than in therapy resistant UW228-3 medulloblastoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 µM) significantly blunted Δ[Ca2+]i, and augmented the ionizing radiation-induced apoptosis but did not significantly modify clonogenicity of medulloblastoma cells. Apoptosis was further enhanced by NCX3 silencing. Conclusions: Na+/Ca2+-exchanger activity significantly counteracts apoptosis but does not significantly affect clonogenicity after radiation of medulloblastoma cells.

scholarly journals Influence of Interferon-γ on Salmonella Typhi Induced Macrophage Apoptosis

2020 ◽  
Vol 9 (2) ◽  
Author(s):  
Fidan I ◽  
Yesilyurt E ◽  
Kalkanci A ◽  
Erdal B ◽  
Gurelik FC ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Annexin V ◽  
Salmonella Typhi ◽  
Interferon Γ ◽  
Salmonella Infection ◽  
Rt Pcr ◽  
Caspase 1 ◽  
Macrophage Apoptosis ◽  
Ifn Γ ◽  
Induced Apoptosis

Introduction: Salmonella Typhi (S.Typhi), which causes typhoid fever, is a widespread pathogen in developing countries. Interferon-gamma (IFN-γ) is a critical cytokine in host defense against Salmonella infection. IFN-γ provides protection against Salmonella infection by inducing macrophage activation. This study was designed to determine the effect of recombinant IFN-γ (rIFN-γ) on S.Typhi induced macrophage apoptosis and to examine the effect of rIFN-g on caspase-1 expression during apoptosis. Materials and Methods: After isolation of macrophages, apoptotic cells were analyzed using both annexin V-FITC detection kit by fl ow cytometry and TUNEL technique. Caspase-1 expression was determined by RT-PCR. Results: The rIFN-γ concentrations of 100 IU/ml ve 1000 IU/ml decreased macrophage apoptosis caused by S.Typhi, 13.1 % and 6.3 % respectively. Conclusion: Consequently, we observed that rIFN-g decreased Salmonella-induced apoptosis and inhibited caspase-1 expression during apoptosis. It is considered that the modulatory effect of IFN-γ on macrophage apoptosis may impact a protective effect during Salmonella infection and this may help to abort invasive S.Typhi infections.

scholarly journals Vitex Rotundifolia Fractions Induced Apoptosis in Human Breast Cancer T-47D Cell Line via Activation of Extrinsic and Intrinsic Pathway

2019 ◽  
Vol 20 (12) ◽  
pp. 3555-3562 ◽  
Author(s):  
Gul-e-Saba Chaudhry ◽  
Rehmat Jan ◽  
Muhammad Naveed Zafar ◽  
Habsah Mohammad ◽  
Tengku Sifzizul Tengku Muhammad
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Human Breast Cancer ◽  
Human Breast ◽  
Intrinsic Pathway ◽  
Induced Apoptosis

The Novel Anti-Leukemic Agent LC-1, Is Preferentially Cytotoxic in CLL Cells Derived from Poor Prognostic Subsets.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2981-2981
Author(s):  
Chris Pepper ◽  
Chris Fegan ◽  
Paul Brennan ◽  
Ken Mills ◽  
Alan K. Burnett
Keyword(s):  
Drug Resistance ◽  
Annexin V ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
The Novel ◽  
Mobility Shift ◽  
Apoptotic Pathway ◽  
Concentration Dependent Manner ◽  
Mobility Shift Assay ◽  
Induced Apoptosis

Abstract Chronic lymphocytic leukemia (CLL) has a variable clinical course but once treatment is required the development of drug resistance often ensues. Therefore, delineation of the biological mechanisms of drug resistance and the development of novel therapies designed to overcome this is an important goal of research into this condition. We have recently shown that the transcription factor NF-κB plays a central role in regulating CLL cell survival and this is mediated, at least in part, through the transactivation of a number of anti-apoptotic genes including Bcl-2. In this pre-clinical study we evaluated the cytotoxic effects of the novel parthenolide analog, LC-1 (Leuchemix Inc.), in primary tumor cells derived from 49 CLL patients (20 treated, 29 untreated). LC-1 induced apoptosis, as assessed by the Annexin V assay, in a concentration-dependent manner (0.1 – 10 μM) in all the CLL samples tested with a mean LD50 value (the concentration of drug required to kill 50% of the cells) of 2.9 μM. The induction of apoptosis was preceded by a marked loss of NF-κB activity, as evidenced by electrophoretic mobility shift assay, and a down regulation in Bcl-2 protein expression. Caspase-3 activation was a consistent feature of LC-1-induced apoptosis pointing to the involvement of the intrinsic apoptotic pathway. Importantly, CD38+ samples (&gt; 30% expression) and those derived from patients with unmutated VH genes were more sensitive to LC-1 (LD50 values = 2.3 μM versus 3.4 μM and 2.4 μM versus 3.2 μM; P = 0.0003 and 0.01 respectively) suggesting that these CLL cells have a disproportionate reliance on NF-κB activity to maintain their survival and proliferative advantage. Taken together our data clearly demonstrates that LC-1 preferentially targets CLL cells from poor prognostic subsets. This unique cytotoxicity profile warrants further investigation and supports the use of this agent in early clinical trials for patients with CLL.

Excessive Oxidative Stress in the Synergistic Effects of Shikonin on the Hyperthermia-Induced Apoptosis

2018 ◽  
Vol 18 (5) ◽  
pp. 322-334 ◽  
Author(s):  
J.-L. Piao ◽  
Y.-J. Jin ◽  
M.-L. Li ◽  
S.A. Zakki ◽  
L. Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Synergistic Effects ◽  
Induced Apoptosis

Synergistic Antitumor Effect of 5-Fluorouracil Combined with Constituents from Pleurospermum lindleyanum in Hepatocellular carcinoma SMMC-7721 Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Xiao-Feng Zhu ◽  
Xiao-Jin Li ◽  
Zhong-Lian Cao ◽  
Xiu-Jie Liu ◽  
Ping Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Effectiveness ◽  
Synergistic Effects ◽  
Folk Medicine ◽  
Inhibitory Effect ◽  
Caspase 9 ◽  
Whole Plant ◽  
Anti Cancer ◽  
Induced Apoptosis

Background: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells. Objective: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms. Methods: Sequential chromatographic techniques were conducted for the isolation studies. The isolates structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression. Results: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP. Conclusion: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

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