Sericin Preparation from Cocoons of Oak Tasar Silkworm Antheraea proylei J. Induces Apoptosis in a Caspase-dependent Manner in A549 and HeLa Cells and Caspase-independent Manner in PC3 Cells

Abstract BackgroundDespite much progress in understanding the biology of cancer disease, advancement in technology for early diagnosis, the expanding array of anticancer drugs, and treatment modalities, the global cancer burden is still significant and increasing. It is estimated that the new cases of cancer in the year 2040 will be 29.4 million per year globally. Sericin, an adhesive protein of silk cocoon, is a potential protein in various biomedical applications including cancer therapeutics. The present study evaluates the anticancer property of sericin prepared from cocoons of Antheraea proylei J. (A. proylei ) against human lung cancer (A549), cervical cancer (HeLa), and prostate cancer (PC3) cell lines. This is the first report of the anti-cancer activity of the non-mulberry silkworm A. proylei. MethodsSericin preparation (SP) was prepared from cocoons of A. proylei J. by the process of the degumming method. The amino acid composition of the SP was determined by HPLC. Cytotoxicity activity was assessed by MTT assay and genotoxicity activity was assessed by comet assay. Cleavage of caspase and PARP proteins and phosphorylation of MAPK pathway members were analyzed by Western blotting. Cell cycle analysis was done by FACS flow cytometry.Results SP causes cytotoxicity to A549, HeLa, and PC3 cell lines with the IC50 values ranging from 3.4-3.9 µg/µl. SP induces apoptosis in a dose-dependent manner through caspase-3 and p38/SAPK/ERK pathways in A549 and HeLa cells whereas in PC3 cells SP induces apoptosis independent of caspase but through p38 pathway. Moreover, in the case of A549 and HeLa cells, SP induces cell cycle arrest at the S phase whereas at the G0 phase in the case of PC3 cells in a dose-dependent manner.ConclusionThe difference in the molecular mechanisms of apoptosis induced by SP in A549 and HeLa cell lines, and in PC3 cell lines may be due to the difference in the genotypes of the cancer cell lines where A549 and HeLa cells are being non-malignant and p53 positive whereas PC3 cell is being malignant and p53 negative. The overall results of the present study envisage the possibility of using SP as an anti-tumorogenic agent.

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Antheraea proylei J. sericin induces apoptosis in a caspase dependent manner in A549 and HeLa cells and caspase independent manner in PC3 cells

10.21203/rs.3.rs-56346/v2 ◽

2021 ◽

Author(s):

Potsangbam Jolly Devi ◽

Asem Robinson Singh ◽

Lisam Shanjukumar Singh ◽

Laishram Rupachandra Singh ◽

Sanjenbam Kunjeshwori Devi

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Hela Cells ◽

Molecular Mechanisms ◽

Human Lung Cancer ◽

Treatment Modalities ◽

Dependent Manner ◽

Pc3 Cells ◽

Mulberry Silkworm ◽

Dose Dependent

Abstract BackgroundIn spite of much progress in understanding the biology of cancer disease, advancement in technology for early diagnosis, the expanding array of anticancer drugs and treatment modalities, the global cancer burden is still significant and increasing. It is estimated that the new cases of cancer in the year 2040 will be 29.4 million per year globally. Sericin, an adhesive protein of silk cocoons has been shown to be a potential protein in various biomedical applications including cancer therapeutics. The present study evaluates the anticancer property of sericin from cocoons of Antheraea proylei J. (SAP) against human lung cancer (A549), cervical cancer (HeLa), and prostate cancer (PC3) cell lines. This is the first report of anti-cancer activity of the non-mulberry silkworm A. proylei J. Methods SAP was prepared from cocoons of A. proylei J. by the process of degumming method. The amino acid composition of SAP was determined by HPLC. Cytotoxicity activity was assessed by MTT assay and genotoxicity activity was assessed by comet assay. Cleavage of caspase and PARP proteins and phosphorylation of MAPK pathway members were analysed by Western blotting. Cell cycle analysis was done by flow cytometery.ResultsSAP causes cytotoxicity to A549, HeLa and PC3 cell lines with the IC50 values ranging from 3.4-3.9 µg/µl. SAP induces apoptosis in a dose-dependent manner through caspase-3 and p38 and ERK pathways in A549 and HeLa cells respectively whereas in PC3 cells, SAP induces apoptosis independent of caspase through p38 pathway. Moreover, in the case of A549 and HeLa cells SAP induces cell cycle arrest at S phase in a dose dependent manner whereas at G0 phase in the case PC3 cells.ConclusionSAP induces apoptosis in A549, HeLa, and PC3. The difference in the molecular mechanisms of apoptosis induced by SAP in A549 and HeLa and in PC3 may be due to the differences in the genotypes of the cancer cell lines. However, further investigation is warranted. The overall results of the present study envisage the possibility of using SAP as anti-tumorigenic agent.

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Macleayins A From Macleaya Promotes Cell Apoptosis Through Wnt/β-Catenin Signaling Pathway and Inhibits Proliferation, Migration, and Invasion in Cervical Cancer HeLa Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.668348 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunmei Sai ◽

Wei Qin ◽

Junyu Meng ◽

Li-Na Gao ◽

Lufen Huang ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Lines ◽

Hela Cells ◽

Luciferase Assay ◽

Signaling Cascade ◽

Migration And Invasion ◽

Potential Candidate ◽

Dependent Manner ◽

Hela Cell Lines

Macleayins A (MA), a novel compound, was isolated from Macleaya cordata (Willd.) R. Br. and Macleaya microcarpa (Maxim.) Fedde. The plant species are the member of Papaveraceae family and have been used traditionally for diverse therapeutic purposes. According to the reported studies, the chemical constituents, as well as crude extracts of these plants, could attenuate the proliferation of several cancer cell lines, such as HL-60, A549, HepG2, and MCF-7. The current study aimed to investigate the anticervical cancer activity of MA and its related molecular mechanism. Isolation of MA was carried out using various column chromatographic methods, and its structure was elucidated with 1H NMR. The cytotoxicity of MA was determined against HeLa cell lines via CCK-8 assay. The cell proliferation, apoptosis, cell cycle, migration, and invasion were measured by EdU labeling, Annexin-V APC/7-AAD double staining, PI staining, and transwell assay, respectively. The protein expression levels of c-Myc, β-catenin, cyclin D1, and MMP-7 in the cells were evaluated by western blotting. The Wnt/β-catenin signaling cascade activation was verified using the Dual-Glo® Luciferase assay. We found that MA inhibited the growth of HeLa cells at 72 h (IC50 = 26.88 µM) via inducing apoptotic process, reduced the proliferation rate by 29.89%, and decreased the cells migration and invasion as compared to the untreated group. It arrested the cell cycle at the G1 phase and its treatment inhibited the expression of related proteins c-Myc, β-catenin, cyclin D1, and MMP-7 in the Wnt/β-catenin signaling cascade. Further, the Wnt/β-catenin signaling cascade activation in MA-treated HeLa cells was attenuated in a dose-dependent manner. These findings demonstrate the anticancer effects of MA on a mechanistic level, thus providing a basis for MA to become a potential candidate drug for resistance of cervical carcinoma.

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Baicalein Inhibits the Proliferation of Cervical Cancer Cells Through the GSK3β-Dependent Pathway

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x15031557924141 ◽

2018 ◽

Vol 26 (4) ◽

pp. 645-653 ◽

Cited By ~ 4

Author(s):

Xiaoling Wu ◽

Zhiqin Yang ◽

Huimin Dang ◽

Huixia Peng ◽

Zhijun Dai

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cyclin D1 ◽

Cancer Cells ◽

Hela Cells ◽

Glycogen Synthase ◽

Dependent Manner ◽

Cervical Cancer Cells ◽

Dose Dependent ◽

Dependent Pathway

Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to possess multiple pharmacological activities, such as anticancer and anti-inflammatory properties. This study investigated the effect of baicalein in cervical cancer cells. Cell growth curve and MTT assay were performed and revealed that baicalein inhibited the proliferation of SiHa and HeLa cells in a dose-dependent manner. We further found that baicalein arrested the cell cycle of SiHa and HeLa cells at the G0/G1 phase by suppressing the expression of cyclin D1 through the downregulation of phosphorylated protein kinase B (p-AKT) and phosphorylated glycogen synthase kinase 3β (p-GSK3β) according to FACS assays and Western blotting. Moreover, when CHIR-99021, a GSK3β inhibitor, was added to baicalein-treated SiHa cells, the expression of cyclin D1 was recovered, and cell proliferation was promoted. In conclusion, these data indicated that baicalein suspended the cell cycle at the G0/G1 phase via the downregulation of cyclin D1 through the AKT‐GSK3β signaling pathway and further inhibited the proliferation of SiHa and HeLa cervical cancer cells.

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Cyclin-Dependent Kinase 4/6 Inhibitor Abemaciclib Exerts Dose-Dependent Cytostatic and Cytocidal Effects on Multiple Myeloma Cells Via Autophagy

Blood ◽

10.1182/blood.v128.22.4478.4478 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4478-4478 ◽

Cited By ~ 1

Author(s):

Noriyoshi Iriyama ◽

Hirotsugu Hino ◽

Shota Moriya ◽

Masaki Hiramoto ◽

Yoshihiro Hatta ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cell Lines ◽

Cell Apoptosis ◽

Annexin V ◽

Myeloma Cell ◽

Parp Cleavage ◽

Dependent Manner ◽

Myeloma Cells ◽

Dose Dependent

Abstract Background:Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of abnormal plasma cells in the bone marrow. D-type cyclins (CCNDs), an important family of cell cycle regulators, are thought to be implicated in multiple myeloma (MM) development because CCNDs are commonly expressed in myeloma cells. CCND is known to positively regulate the cell cycle from G1 to S-phase initiation by binding to cyclin-dependent kinase (CDK) 4/6, resulting in potentiation of myeloma cell growth. These findings suggest a possible role for CDK4/6-targeting therapy in MM, yet the details remain incompletely understood. In this regard, we investigated the biological activity of abemaciclib, a potent, highly selective CDK4/6 inhibitor, in myeloma cell lines, to elucidate the mechanisms underlying the involvement of the CCND-CDK4/6 complex in cell cycle regulation and survival. Methods:The effects of abemaciclib on myeloma cells were investigated using three myeloma cell lines, KMS12-PE (CCND1-positive and CCND2-negative), RPMI8226 (CCND1-negative and CCND2-positive), and IM-9 (both CCND1- and CCND2-positive). Cell growth was assessed by trypan blue exclusion assay. Cell cycle analysis was performed using propidium iodide (PI) and apoptosis was measured using annexin V/PI staining via flow cytometry. Cell cycle regulated proteins, including p21 and p27, and phosphorylated proteins, including STAT1, STAT3, ERK, JNK, p38, and AKT, were evaluated using a phospho-flow method. Autophagy was assessed using CYTO-ID via flow cytometry. PARP cleavage was investigated via western blotting. Clarithromycin, an antibiotic agent belonging to the macrolide class, was used as an autophagy inhibitor. Results:Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all the cell lines evaluated, with significant differences seen at a concentration of 320 nM. Annexin V/PI staining revealed that 1 μM abemaciclib showed little or no effect on apoptosis, but 3.2 μM abemaciclib induced apparent myeloma cell apoptosis, with an increase in both the early and late apoptotic fractions. Therefore, 1 and 3.2 μM of abemaciclib were used in subsequent experiments for the assessment of cell growth and apoptosis, respectively. Cell cycle analyses revealed that 1 μM abemaciclib increased the fraction of cells in G0/G1 phase and decreased the fraction in S-G2/M phase. Furthermore, this effect was associated with the upregulation of p21 and p27 in the evaluated myeloma cells. PARP cleavage was observed in KMS12-PE cells treated with 3.2 μM abemaciclib, but not 1 μM, suggesting a close connection between the degree of PARP cleavage and apoptosis in myeloma cells. Importantly, abemaciclib induced autophagy in a dose-dependent manner. However, no apparent inhibitory effect on the autophagy-related phosphorylated proteins STAT1 (Y701), STAT3 (Y705), ERK (T202/Y204), JNK (T183/Y185), p38 (T180/Y182), or AKT (Y315) was observed in myeloma cells treated with 3.2 μM abemaciclib. To investigate the role of abemaciclib-induced autophagy on myeloma cell apoptosis, we further assessed the apoptotic effect of 3.2 μM abemaciclib or 50 μg/mL clarithromycin, alone or in combination. Clarithromycin did not induce apoptosis of myeloma cells. Importantly, clarithromycin treatment in combination with abemaciclib attenuated the apoptotic effect of abemaciclib. Discussion & Conclusions: Although the underlying mechanisms conferring the level of CCND expression are known to differ greatly (e.g., CCND translocation, hyperdiploidy, or activation of upstream pathways of CCND transcription), the results of the current study indicate that the CCND-CDK4/6 complex is closely involved in myeloma cell growth and survival regardless of the CCND family member present. In addition, we demonstrate that abemaciclib exerts multiple effects, such as myeloma cell apoptosis, via the PARP pathway or autophagy, as well as cell cycle regulation. Because abemaciclib in combination with clarithromycin inhibits myeloma cell apoptosis, the autophagy induced by abemaciclib is considered to have a critical role in the induction of apoptosis, so-called "autophagic cell death." These results provide novel insights into a possible therapeutic approach using abemaciclib to target CDK4/6 in patients with MM, and offer new possibilities for combination therapy with CDK4/6 inhibitors and autophagy regulators. Disclosures Iriyama: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Hatta:Novartis Pharma: Honoraria.

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Decorin induced by progesterone plays a crucial role in suppressing endometriosis

Journal of Endocrinology ◽

10.1530/joe-14-0393 ◽

2014 ◽

Vol 223 (2) ◽

pp. 203-216 ◽

Cited By ~ 13

Author(s):

Yoshihiro Joshua Ono ◽

Yoshito Terai ◽

Akiko Tanabe ◽

Atsushi Hayashi ◽

Masami Hayashi ◽

...

Keyword(s):

Cell Cycle ◽

Mrna Expression ◽

Cell Lines ◽

Stromal Cells ◽

Crucial Role ◽

Dependent Manner ◽

Endometrial Stromal Cells ◽

Endometrial Cells ◽

Cycle Arrest ◽

Dose Dependent

Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on the in vitro proliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examined DCN mRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed that DCN mRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.

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Advanced Glycation End Products (AGEs)-Mediated Cell Growth of Human Acute Myelogenous Leukemia Via Mitogen-Activated Protein (MAP) Kinase Pathways.

Blood ◽

10.1182/blood.v106.11.2762.2762 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2762-2762

Author(s):

Ju Young Kim ◽

Hyun Ki Park ◽

Jin Sun Yoon ◽

Eun Shil Kim ◽

Kwang Sung Ahn ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cell Lines ◽

Cellular Proliferation ◽

Myelogenous Leukemia ◽

Dependent Manner ◽

Glycation End Products ◽

Mitogen Activated Protein ◽

Acute Myelogenous ◽

Dose Dependent

Abstract Advanced glycation end products (AGEs) are products of non-enzymatic glycation/oxidation of proteins/lipids that accumulate slowly during natural aging and at a much accelerated rate in a variety of disorders such as diabetes, renal failure, and Alzheimer’s disease. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signaling, activation of transcription factors and subsequent gene expression in vitro and in vivo. Most of the biologic activities associated with AGEs have been transduced by receptor for AGE (RAGE). Recently, AGEs are known to be in association with diverse cancers in terms of cellular proliferation and metastasis. However, little is known about the role of AGEs in acute myelogenous leukemia (AML). Here we examined the effects of the AGEs-RAGE interaction on the cell proliferation and intracellular signaling of AGEs in human leukemia cell lines. Expression of RAGE was observed in 8 AML cell lines examined, and up-regulated by treatment of AGE. AGE induced the proliferation of AML cell lines, HL60 and HEL, in a dose-dependent manner. Treatment with 5 μM of antisense S-ODN for RAGE did effectively inhibit cell growth of HEL cells. Exposure of HL60 and HEL with AGE induced a significant increase in the numbers of cells in S phase of cell cycle in a dose-dependent manner. AGE enhanced the expression of cell cycle regulatory proteins such as cyclin-dependent kinase (CDK) 2/4/6, cyclin D1/E/B in a dose- and a time-dependent manner. In addition, the protein levels of the cyclin-dependent kinase inhibitor (CDKI), p21 and p27, were decreased by 24 hr exposure of AGE from 10 to 200 μg/ml in HEL. Furthermore, treatment of HEL with 200 μg/ml of AGE triggered activation of mitogen-activated protein (MAP) kinases, Erk, Akt, and p38, pathways and in nuclear translocation of transcription factors NF-kB. These results indicated that AGE induced the cell growth of human AML cells, HL60 and HEL, via augmentation of cell cycle and activation of MAPK kinase pathways. Up-regulation of RAGE by exposure of AGE suggested that cellular proliferation of AML cells might be mediated in autocrine fashion.

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Valproic Acid Inihibts Histone Deacetylases and Proliferation and Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.5165.5165 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5165-5165

Author(s):

Martin Kaiser ◽

Ulrike Heider ◽

Ivana Zavrski ◽

Jan Sterz ◽

Kurt Possinger ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Valproic Acid ◽

Cell Lines ◽

Myeloma Cell ◽

G1 Phase ◽

Dependent Manner ◽

Myeloma Cells ◽

Cycle Arrest ◽

Dose Dependent

Abstract Multiple myeloma remains an incurable disease in the majority of the patients and novel treatment strategies are urgently needed. A new class of drugs, the histone deacetylase (HDAC) inhibitors take influence in epigenetic modifications and have antiproliferative effects in some malignancies. Valproic acid (VPA) is an anticonvulsant drug and was recently shown to inhibit HDACs and suppress tumor growth. The drug is currently being evaluated in clinical studies in acute myeloid leukemia. Its effects on myeloma cells are unknown. The aim of this study was to evaluate the effects of VPA on proliferation, apoptosis and HDAC inhibition in multiple myeloma cell lines as well as in sorted human bone marrow multiple myeloma cells. Myeloma cell lines, OPM-2, NCI-H929, LP-1, and freshly isolated multiple myeloma cells from bone marrow aspirates were exposed to different concentrations of VPA for 4 to 72 hours. Cell proliferation, cell cycle distribution and apoptosis were assayed in reaction to the treatment. Proliferation decreased noticeably and apoptosis was induced in a dose-dependent manner in multiple myeloma cell lines as well as in freshly sorted primary myeloma cells. After 48 hours of incubation with VPA at 1 mM, approximately 46%, 52% and 25% of OPM-2, NCI-H929 and LP-1 cell lines had undergone specific apoptosis, respectively. Freshly sorted primary bone marrow myeloma cells from patients showed also specific apoptosis. In cell cycle analysis by flow cytometry, the population of cells in the G0/G1 phase increased, whereas cells in the S phase decreased in a time and dose dependent manner. Incubation of the cell line OPM-2, for example, with 1 mM VPA for 48 hours decreased the proportion of cells in the S phase from 39 % to 6 % of the total cell count and increased cells in the G0/G1 phase from 49 % to 85 %. Acetylation of histones and expression of cyclin D1 and the cell cycle regulators p21 and p27 were studied by western blot. Histone acetylation and p21 concentrations increased after VPA treatment whereas levels of p27 remained constant. A decrease in cyclin D1 concentrations was observed. Subapoptotic doses of VPA significantly decreased the production of VEGF in OPM-2 cell line. These data show that treatment with valproic acid effectively inhibits histone deacetylase activity, leading to the accumulation of acetylated histones in multiple myeloma cells. Parallel upregulation of cell cycle inhibitors like p21WAF1 was observed, together with a reduction of cyclin D1 levels. Myeloma cell proliferation was inhibited in a time and dose dependent manner and cell cycle arrest in the G0/G1 phase was induced by VPA treatment. VPA potently induced apoptosis in all human myeloma cell lines as well as in sorted primary multiple myeloma cells in a dose and time dependent manner. These results show for the first time that VPA acts as an HDAC inhibitor in multiple myeloma cells, induces G1 cell cycle arrest, potently inhibits tumor growth and markedly induces apoptosis. In addition to its direct antitumor effect, valproic acid may exert an antiangiogenic effect by reducing VEGF production in myeloma cells. These data provide the framework for clinical studies with valproic acid in multiple myeloma.

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Sulforaphane Causes Cell Cycle Arrest and Apoptosis in Human Glioblastoma U87MG and U373MG Cell Lines under Hypoxic Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms222011201 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11201

Author(s):

Giulia Sita ◽

Agnese Graziosi ◽

Patrizia Hrelia ◽

Fabiana Morroni

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Hypoxic Condition ◽

Primary Brain Tumor ◽

Dependent Manner ◽

Hypoxic Conditions ◽

Cycle Arrest ◽

Extracellular Signal ◽

Dose Dependent

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor. The median survival rate from diagnosis ranges from 15 to 17 months because the tumor is resistant to most therapeutic strategies. GBM exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, has already demonstrated the ability to inhibit cell proliferation, by provoking cell cycle arrest, and leading to apoptosis in many cell lines. In this study, we investigated the antineoplastic effects of SFN [20–80 μM for 48 h] in GBM cells under normoxic and hypoxic conditions. Cell viability assays, flow cytometry, and Western blot results revealed that SFN could induce apoptosis of GBM cells in a dose-dependent manner, under both conditions. In particular, SFN significantly induced caspase 3/7 activation and DNA fragmentation. Moreover, our results demonstrated that SFN suppressed GBM cells proliferation by arresting the cell cycle at the S-phase, also under hypoxic condition, and that these effects may be due in part to its ability to induce oxidative stress by reducing glutathione levels and to increase the phosphorylation of extracellular signal-regulated kinases (ERKs). Overall, we hypothesized that SFN treatment might serve as a potential therapeutic strategy, alone or in combination, against GBM.

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Effect of berubicin, the 4'-o-benzylated doxorubicin analog, on growth inhibition and apoptosis in multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18557 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18557-e18557 ◽

Cited By ~ 2

Author(s):

Michael Wang ◽

Luhong Sun ◽

Izabela Fokt ◽

Liang Zhang ◽

Arumugam Jayakumar ◽

...

Keyword(s):

Cell Cycle ◽

Clinical Trial ◽

Multiple Myeloma ◽

Growth Inhibition ◽

Cell Lines ◽

Bone Marrow Cells ◽

Cancer Center ◽

Dependent Manner ◽

M Cell ◽

Dose Dependent

e18557 Background: Doxorubicin (DOX), an anthracycline, topoisomerase II inhibitor, is routinely used for hematologic malignancies including multiple myeloma (MM); however, its efficacy is limited by drug resistance and cardiotoxcity. To overcome these limitations, we designed, synthesized and tested Berubicin (BRN). BRN has been evaluated in clinical trials in neuroblastoma multiforme. It is a representative of a novel class of mechanistically altered anthracycline analogs. The data obtained from this study will serve as the basis for the rapid translation of BRN from the bench to the clinic in a phase I clinical trial for patients with MM at MD Anderson Cancer Center. Methods: We investigated the effects of BRN, DOX and Bortezomib (BTZ) in 3 human MM cell lines, MM1S, ARP-1, U266, and freshly isolated primary samples from patients with MM. MM cells were treated with BRN, DOX, and BTZ. The effects of these compounds on cell proliferation, apoptosis, and the cell cycle were analyzed using MTS assay and flow cytometry analysis. Results: BRN potently inhibited the growth of the established MM cell lines, as well as the freshly isolated primary MM cells in a dose-dependent manner. It showed growth inhibition at IC50 of 5.99 nM (U266), 5.21 nM (MM1S) and 3.99 nM (ARP-1), and was more potent than doxorubicin (IC50 14.63 nM, 7.24 nM and 11.06 nM) and bortezomib (IC50 304.9 nM, 15.47 nM and 53.19 nM). In contrast, BRN did not affect the proliferation of patient-derived normal bone marrow cells (CD138- cells) at the concentrations that were lethal to MM cells. Conclusions: Berubicin not only induced apoptosis in 3 cell lines in dose-dependent manners but also induced G2/M cell cycle arrest in 3 cell lines. In conclusion, BRN was effective against MM cells in vitro and will be applied to our planned clinical trial.

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Construction of Radiation Surviving/Resistant Lung Cancer Cell Lines with Equidifferent Gradient Dose Irradiation

Dose-Response ◽

10.1177/1559325820982421 ◽

2020 ◽

Vol 18 (4) ◽

pp. 155932582098242

Author(s):

Lijuan Wang ◽

Shangbiao Li ◽

Xiaoxia Zhu

Keyword(s):

Lung Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Radiation Resistance ◽

Cancer Cell Lines ◽

Human Lung Cancer ◽

Dependent Manner ◽

Lung Cancer Cell ◽

Dose Irradiation ◽

Dose Dependent

Radiotherapy plays an increasingly crucial role in the treatment of non-small cell lung cancer (NSCLC). Local tumor recurrence and tumor progression caused by intratumoral heterogeneity induced radiotherapy resistance remain the primary causes of radiotherapy failure. However, the lack of a suitable cell line model has hampered the exploration of the dynamic mechanisms of radiation resistance. We established 3 groups of equidifferent gradient dose irradiation surviving/resistant human lung cancer cell lines based on A549, H520, and H460 cells with clinical conventional fractionated radiotherapy (CFRT) (2 Gy × 20 F, 2 Gy × 30 F, and 2 Gy × 40 F). The radiosensitivity of the cells was detected by clone formation assay, EDU cell proliferation assay, neutral comet assay, and γ-H2AX immunofluorescence staining. The radiosensitivity and proliferation viability were increased in a received dose-dependent manner. Compared with parental cells, DNA double-strand breaks (DSBs) in cell lines that received higher-dose irradiation were significantly reduced. We successfully constructed equidifferent gradient dose irradiation surviving/resistant NSCLC cell lines whose radiation surviving and resistant abilities were increased in a received dose-dependent manner. This preclinical cell model could be used to dynamically observe and detect the radiation surviving/resistant biomarkers during radiotherapy stress, elucidate the mechanism of radiation resistance.

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