scholarly journals Enhancing Radiotherapy Using Ultrasound And Microbubbles With Gold Nanoparticles

2021 ◽  
Author(s):  
Amanda T.L. Tran
Keyword(s):  
Gold Nanoparticles ◽  
Cell Death ◽  
Radiation Dose ◽  
Cell Viability ◽  
Therapeutic Effect ◽  
Combined Treatment ◽  
Genetic Material ◽  
Chemotherapeutic Agents ◽  
Enhanced Permeability And Retention ◽  
Local Radiation

Gold nanoparticles (AuNPs) have been shown to enhance the local radiation dose in tumour mice models. Although AuNPs can be delivered to tumours through enhanced permeability and retention (EPR) effect, delivering of AuNP for therapeutic effect has been proven to be challenging. The application of ultrasound and microbubbles (USMB) has been shown to increase the delivery of genetic material, macromolecules, and chemotherapeutic agents. The hypothesis driving this research is that ultrasound and microbubbles can increase uptake of AuNPs in cells. The results suggest that AuNPs, and USMB aid in its delivery to increase cell death upon irradiation. An improvement of ~ 22 fold was observed with the combined treatment compared to radiation only, implying synergism. In addition, USMB and radiation exhibited an increase in cell death. Cell viability was ~3-4% and is dependent on AuNP concentration, shape and location. Further investigation of this concept was done

scholarly journals Enhancing Radiotherapy Using Ultrasound And Microbubbles With Gold Nanoparticles

2021 ◽  
Author(s):  
Amanda T.L. Tran
Keyword(s):  
Gold Nanoparticles ◽  
Cell Death ◽  
Radiation Dose ◽  
Cell Viability ◽  
Therapeutic Effect ◽  
Combined Treatment ◽  
Genetic Material ◽  
Chemotherapeutic Agents ◽  
Enhanced Permeability And Retention ◽  
Local Radiation

Gold nanoparticles (AuNPs) have been shown to enhance the local radiation dose in tumour mice models. Although AuNPs can be delivered to tumours through enhanced permeability and retention (EPR) effect, delivering of AuNP for therapeutic effect has been proven to be challenging. The application of ultrasound and microbubbles (USMB) has been shown to increase the delivery of genetic material, macromolecules, and chemotherapeutic agents. The hypothesis driving this research is that ultrasound and microbubbles can increase uptake of AuNPs in cells. The results suggest that AuNPs, and USMB aid in its delivery to increase cell death upon irradiation. An improvement of ~ 22 fold was observed with the combined treatment compared to radiation only, implying synergism. In addition, USMB and radiation exhibited an increase in cell death. Cell viability was ~3-4% and is dependent on AuNP concentration, shape and location. Further investigation of this concept was done

Mevalonate pathway inhibitors in the treatment of B-cell chronic lymphocytic leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6561-6561
Author(s):  
Ravi Kiran Bobba ◽  
Indira Benakanakere ◽  
Smitha Bearelly ◽  
Monica Arya ◽  
Richard Sleigtholm ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
B Cell ◽  
Combination Treatment ◽  
Mevalonate Pathway ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

6561 Background: B-cell chronic lymphocytic leukemia (CLL) cells are arrested in G0/G1 phase of the cell cycle and are resistant to programmed cell death, hypothesized to contribute to the resistance of CLL cells to standard chemotherapy with curative intent. Methods: Mec-2 cells and Wac-3 cells are CLL cells that have been shown to be resistant to fludarabine and rituximab. We tested a novel enzyme inhibitor’s ability to render CLL cells sensitive to fludarabine and rituximab. Results: BIBB515, a lanosterol synthase inhibitor, at a concentration of 10μM, was able to reduce the cell viability from 82% in controls to 65% after 72 hours. Fludarabine 10μM alone did not reduce the cell viability, 82 % in controls compared to 80%. BIBB515+ fludarabine treatment for 72 hours, at the dose of 10μM each decreased the cell viability to 37%. Cell proliferation by MTT assay was 0.66±0.010 in control compared to 0.37±0.01 in BIBB515+fludarbine and 0.21±0.01 in BIBB515+ fludarabine+ rituximab. There is a 68% down-regulation of cell proliferation using this treatment. There was a two fold induction of CD 20 with combination treatment, and BIBB515 treatment. The mechanism of cell death in the combination treatment of BIBB515 and fludarabine may be due to the up regulation of cell surface marker CD-20. WAC-3 is another CLL cell line that is sensitive to fludarabine, and resistant to rituximab. BIBB515 sensitizes WAC-3 cells to CD 20 antibody rituximab. There is a 68.7% decrease in cell proliferation with combination treatment of BIBB515 and rituximab. Proliferation of Mec-2 cells were inhibited by 60µM and 30µM terbinafine. Ro-48-8071, showed dose-dependent activity, alone or in combination to fludarabine was seen to induce cell death in Mec-2 cells. Fludarabine alone did not have any effect on these cells. Conclusions: Inhibitors of the mevalonate pathway make resistant CLL cells sensitive to current chemotherapeutic agents. Exploiting this mechanism could alter the current treatment regimens, leading to control of the disease in advanced stages by either inducing the leukemic cells to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.

scholarly journals The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

2017 ◽  
Vol 43 (1) ◽  
pp. 108-119 ◽  
Author(s):  
Giada Catalogna ◽  
Cristina Talarico ◽  
Vincenzo Dattilo ◽  
Vincenzo Gangemi ◽  
Ferdinando Calabria ◽  
...  
Keyword(s):  
Cell Death ◽  
Glioblastoma Multiforme ◽  
Cell Viability ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Malignant Gliomas ◽  
P53 Expression ◽  
Radio Therapy

Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. Results: We demonstrate here, that i) 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells.

scholarly journals Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell death

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Annemarie Ackermann ◽  
Aysun Çapcı ◽  
Michael Buchfelder ◽  
Svetlana B. Tsogoeva ◽  
Nicolai Savaskan
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cell Viability ◽  
Malignant Tumors ◽  
Glioma Cells ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Tumor Cell Death ◽  
Combinational Treatment ◽  
The Impact

AbstractGliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents.

Prelinical Evaluation of Lyn Kinase Inhibition for the Treatment of B Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3447-3447
Author(s):  
Vamsidhar Velcheti ◽  
Li Li ◽  
Joseph Philips ◽  
Jyotsna Fuloria ◽  
Francis R Rodwig ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Viability ◽  
B Cell ◽  
Combined Treatment ◽  
Chemotherapeutic Agents ◽  
Negative Regulator ◽  
Cell Leukemia ◽  
Lyn Kinase ◽  
Control Peptide ◽  
Inhibitor Peptide

Abstract Abstract 3447 Poster Board III-335 B-CLL is characterized by the accumulation of mature B lymphocytes incapable of undergoing apoptosis. Although several mechanisms have been implicated in the apoptotic defects in B-CLL cells, the signal transduction pathways underlying these defects remain unresolved. Lyn kinase is known to be a negative regulator of apoptosis, and is linked to chemo-resistance. Our preliminary study indicated that Lyn activity was 4- to 7-fold higher in primary B cells from six randomly-selected B-CLL patients than in normal B cells from healthy donors. Treatment of the B-CLL cells for 4 h with 10 μM concentration of a Lyn-specific inhibitor peptide targeting a unique interaction site within Lyn (Cancer Res. 2004;64:1058) resulted in 40 to 50% inhibition of Lyn kinase activity compared to negligible inhibition with control peptide. Further, treatment of the B-CLL cells for 16 to 20 h with the Lyn inhibitor peptide at 5 μM and 10 μM concentrations, decreased the cell viability by ∼25% and ∼50%, respectively, compared with no peptide or the control peptide. Fludarabine is one of the key chemotherapeutic agents for B-CLL and is known to induce cell death by apoptosis. The combined treatment with Lyn inhibitor peptide (5 μM) and fludarabine (2 μg/ml), decreased cell viability by ∼50% compared to ∼25% decrease with fludarabine or Lyn inhibitor peptide alone. In addition, the combined treatment showed ∼75% increase in caspase-3/7 activity compared to ∼25% increase with the Lyn inhibitor peptide or fludarabine alone. Because, overexpression of antiapoptotic proteins is correlated with apoptotic resistance of B-CLL cells, we examined the effect of Lyn inhibitor peptide on the changes in the expression of antiapoptotic genes, myeloid cell leukemia-1 (Mcl-1), x-linked inhibitor of apoptosis (XIAP), and B-cell leukemia/lymphoma-2 (Bcl-2). Treatment of B-CLL cells with 10 μM Lyn inhibitor peptide for 16 to 20 h resulted in more than 50% decreases in the expression of all the three antiapoptotic genes. Further, the Lyn inhibitor peptide markedly inhibited NF-κB activation (∼60%) and VEGF production (∼80%), both strongly implicated in the apoptotic resistance of B-CLL cells. Collectively, our results suggest that targeting Lyn kinase pathway with a clinically relevant Lyn kinase inhibitor may have a therapeutic potential for B-CLL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bcl-2 and Bcl-XL Can Differentially Block Chemotherapy-Induced Cell Death

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1208-1216 ◽  
Author(s):  
Philip L. Simonian ◽  
Didier A.M. Grillot ◽  
Gabriel Nuñez
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Viability ◽  
Wide Spectrum ◽  
Present Report ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Phase ◽  
Lymphoid Cells ◽  
Cycle Phase ◽  
Γ Irradiation

Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and γ-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or γ-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by γ-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against γ-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.

Activation of Myosin Phosphatase by Epigallocatechin-Gallate Sensitizes THP-1 Leukemic Cells to Daunorubicin

2020 ◽  
Vol 20 ◽  
Author(s):  
Emese Tóth ◽  
Ferenc Erdődi ◽  
Andrea Kiss
Keyword(s):  
Tumor Suppressor ◽  
Cell Viability ◽  
Combined Treatment ◽  
Epigallocatechin Gallate ◽  
Chemotherapeutic Agents ◽  
Leukemic Cells ◽  
Regulatory Subunit ◽  
Regulatory Function ◽  
Myosin Phosphatase ◽  
Tumor Suppressor Proteins

Background: The Myosin Phosphatase (MP) holoenzyme is composed of a Protein Phosphatase type 1 (PP1) catalytic subunit and a regulatory subunit termed Myosin Phosphatase Target subunit 1 (MYPT1). Besides dephosphorylation of myosin, MP has been implicated in the control of cell proliferation via dephosphorylation and activation of the tumor suppressor gene products, retinoblastoma protein (pRb) and merlin. Inhibition of MP was shown to attenuate the drug-induced cell death of leukemic cells by chemotherapeutic agents, while activation of MP might have a sensitizing effect. Objective: Recently, Epigallocatechin-Gallate (EGCG), a major component of green tea, was shown to activate MP by inducing the dephosphorylation of MYPT1 at phospho-Thr696 (MYPT1pT696), which might confer enhanced chemosensitivity to cancer cells. Methods: THP-1 leukemic cells were treated with EGCG and Daunorubicin (DNR) and cell viability was analyzed. Phosphorylation of tumor suppressor proteins was detected by Western blotting. Results: EGCG or DNR (at sub-lethal doses) alone had moderate effects on cell viability, while the combined treatment caused a significant decrease in the number of viable cells by enhancing apoptosis and decreasing proliferation. EGCG plus DNR decreased the phosphorylation level of MYPT1pT696, which was accompanied by prominent dephosphorylation of pRb. In addition, significant dephosphorylation of merlin was observed when EGCG and DNR were applied together. Conclusion: Our results suggest that EGCG-induced activation of MP might have a regulatory function in mediating the chemosensitivity of leukemic cells via dephosphorylation of tumor suppressor proteins.

scholarly journals Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Ho-Min Yu ◽  
Do Kyoung Kim ◽  
Hye Jin Seo ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Leukemia Cell ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Distribution ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. Methods Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. Results The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

scholarly journals Bcl-2 and Bcl-XL Can Differentially Block Chemotherapy-Induced Cell Death

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1208-1216 ◽  
Author(s):  
Philip L. Simonian ◽  
Didier A.M. Grillot ◽  
Gabriel Nuñez
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Viability ◽  
Wide Spectrum ◽  
Present Report ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Phase ◽  
Lymphoid Cells ◽  
Cycle Phase ◽  
Γ Irradiation

Abstract Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and γ-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or γ-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by γ-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against γ-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.

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