scholarly journals Comparative evaluation of the effectiveness of methods for certification of transplanted cell lines

2021 ◽  
Author(s):  
E.V. Markova ◽  
V.T. Nochevny ◽  
B.L. Manin ◽  
I.N. Matveeva
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Lines ◽  
Traditional Method ◽  
Biological Properties ◽  
International Standards ◽  
Growth Potential ◽  
Wide Range

The article presents the results of certification of two trofovariants of MDVK cell lines with the help of traditional method and flow cytometry. Research object was the test cultures MDBK-E and MDBK-B, which passed 30 and 43 passages, respectively, after cryopreservation. The traditional method of attestation of transplanted cell lines, widely used in practice, is rather laborious and requires significant expenditures of labor, money and time. The flow cytometry method is based on a wide range of cytochemical and fluorescent methods for the analysis of sizes, granularity, phases of the cell cycle, structural components (DNA, RNA, protein), cell apoptosis and a number of other indicators. It was experimentally established that the sublines of MDBK-E and MDBK-B cells differed in cultural, cytomorphological and karyological parameters, as well as in contamination by foreign agents and sensitivity to parainfluenza-3 viruses and infectious rhinotracheitis in cattle. Analysis of histograms of cell distribution depending on the DNA content showed that the studied lines MDBK-E and MDBK-B did not exceed the standard indicator in terms of apoptosis and were at the level of 3,9 and 6,8%, respectively. Cells of the MDBK-E line did not contain viral and mycoplasma contamination, were characterized by a pronounced growth potential, retained the original cell morphology and were the most promising substrate for the production of antigens of parainfluenza-3, infectious rhinotracheitis in cattle. Analysis of granularity distribution results testified to the violation of the division processes and the appearance in the population of the subline MDBK-B of abnormal cells, as well as inadequate conditions for maintaining the test culture. It has been established that the flow cytometry method is objective and quite promising in the selection of culture models that meet the requirements of domestic and international standards. The revealed correlation between the magnitude of apoptosis, cultural properties and parameters of the cell cycle makes it possible to assess the biological properties of the producer culture as one of the leading factors in the change in programmed cell death. Changes the index of programmed cell death underlies a number of important pathological conditions and degenerative processes.

scholarly journals JX06, a Novel PDK1 Inhibitor, Induces Myeloma Cell Apoptosis By Metabolic Reprogramming and Works Synergistically with Bortezomib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1814-1814
Author(s):  
Takayuki Sasano ◽  
Saki Kushima ◽  
Matsushita Yutaka ◽  
Masao Matsuoka ◽  
Hiroyuki Hata ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Pyruvate Dehydrogenase ◽  
Research Funding ◽  
Caspase 3 ◽  
Low Concentrations

Background: Despite the efficacy of novel agents, multiple myeloma (MM) is still an incurable disease. In order to achieve a cure, it is necessary to develop new therapeutic drugs, which target different pathways from the present anti-MM agents. PDK1 (pyruvate dehydrogenase kinase 1) is a glucose metabolism-related protein often induced by HIF-1. PDK1 inactivates PDH (pyruvate dehydrogenase) through phosphorylation, leading to enhanced glycolysis in the cytoplasm and suppression of oxidative phosphorylation in the mitochondria. PDK1 that is highly expressed in plasma cells is a downstream target of IRF4. We previously reported that PDK1 inhibition is a potent therapeutic strategy in MM (Fujiwara S et al. Br. J. Cancer; 108 (1): 170-178. 2013). However, PDK1 inhibitors, which are effective at low concentrations, are limited at present, making PDK1 inhibition difficult to apply in the clinic. In the present study, we examined the efficacy and mechanism of action of JX06, a novel PDK1 inhibitor, against MM cells. Materials and methods: MM cell lines (NCI-H929,KMS-12PE,KMS-12BM,U266, KMM1, RPMI-8226) were treated with PDK1 inhibitor, JX06, in vitro. Caspase inhibitor, Z-VAD-FMK, was used in combination with JX06 to study the mechanism of JX06 induced MM cell death. Mitochondrial pyruvate carrier (MPC) inhibitor, UK5099, was utilized to block pyruvate transportation into the mitochondria. Bortezomib was used in combination with or without JX06. Growth inhibition of MM cell lines by JX06 were examined by WST-8 assay. Cytotoxicity of primary MM cells by JX06 was examined using flow cytometry after staining with 7AAD. Caspase 3 activity and PDH phosphorylation of MM cell lines were determined by Western blot. Cell cycle analysis of MM cell lines treated with or without JX06 was performed by flow cytometry using BrdU. Detection of apoptosis in MM cell lines were examined by Annexin V and PI staining followed by flow cytometry analysis. Results: JX06 suppressed cell growth of various MM cell lines and primary myeloma cells at low concentrations (0.5-1.0 µM). MM cell death by JX06 accompanied caspase 3 activation and this cell death was suppressed under addition of Z-VAD-FMK, indicating that JX06 induced apoptosis in MM cells. Moreover, phosphorylation of PDH, known as a target of PDK1, was significantly suppressed under JX06 treatment, demonstrating that indeed JX06 exerts anti-MM effect by inhibiting PDK1-PDH pathway. Addition of UK5099 to JX06 suppressed JX06-induced MM cell death, demonstrating that the efficacy of JX06 depends on pyruvate transported into the mitochondria through MPC. There was no significant difference in cell cycle distribution between JX06 treated MM cells compared to control, suggesting that JX06 exerts cytotoxicity independent of cell cycle phase. Moreover, significant increase of cell death was observed in NCI-H929 cell line treated in combination with 0.25 µM JX06 and 2.5 nM bortezomib, although bortezomib alone at concentration of 2.5 nM didn't induce cell death. Conclusion: We demonstrated that JX06 could induce apoptosis of MM cell lines and primary MM cells by inhibiting PDK1. JX06-induced MM cell death is mediated by metabolic shift from glycolysis in the cytoplasm to oxidative phosphorylation in the mitochondria (Fig. 1). Considering its efficacy and the distinct mechanism of action from the current anti-MM agents, JX06 can be a promising anti-MM agent. Furthermore, JX06 not only works as single agent, but can also enhance the efficacy of current anti-MM drugs, suggesting this combination lead to better treatment response and less toxicity. Disclosures Matsuoka: Kyowa Kirin Co., Ltd.: Research Funding; Bristol-Myers Squibb Corp.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria.

scholarly journals CC12 Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Glioblastoma Cell Lines and Mouse Xenograft Model

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1793
Author(s):  
Li-Yun Fann ◽  
Jui-Hu Shih ◽  
Jen-Ho Tseng ◽  
Hsu-Shan Huang ◽  
Sheng-Huang Hsiao
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Cell Lines ◽  
Mtt Assay ◽  
Xenograft Model ◽  
Tumor Cell Death ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Among central nervous system tumors, glioblastoma (GBM) is the most common and the most malignant type. Even under current standard treatments, the overall survival rate is still low and the recurrence rate is high. Therefore, developing novel and effective therapy is urgently needed. CC12, a synthesized small molecule, was evaluated for the potential anti-GBM effects in two GBM cell lines, U87MG and U118MG. The observations of cell morphology, MTT assay, flow cytometry-based apoptosis after CC12 treatment, were conducted. Western blot was performed for the investigation of the apoptotic mechanism. Positron emission tomography scan analysis and bioluminescent imaging assay using a mouse xenograft model were performed for the effect of CC12 in vivo. After treated by 10 μM CC12 for 24 h, both U118MG and U87MG cells showed tumor cell death. MTT assay results showed that the survival rates decreased when the CC12 concentrations or the treatment periods increased. Ki-67 expression and flow cytometry results indicated that the proliferation was inhibited in GBM cells, and G1 phase arrest was shown. The results of 7-AAD, Br-dUTP, and JC-1 staining all showed the apoptosis of GBM cells after CC12 treatment. Increased γH2AX, caspase-3, and poly (ADP-ribose) polymerase (PARP) levels meant the DNA damage, and increased Bcl2 family proteins after CC12 treatment indicated the intrinsic apoptotic pathway was involved in CC12 induced apoptosis. Furthermore, CC12 can induce the decrease of tumor prognostic marker DcR3. In vivo experiment results showed the effect of CC12 on tumor size reduction of CC12. In addition, the ability to cross the brain–blood barrier of CC12 was also confirmed. CC12 may have anti-tumor ability through the regulation of cell cycle and apoptosis in vitro and in vivo.

scholarly journals Derived from a Platform of Innovative Therapeutic Molecular Clusters (TMC), Ag5 Is a Highly Potent and Differentiated Molecule That Promises to be Efficacious in Hard-to-Treat Hematological Cancers

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-23
Author(s):  
Vanesa Porto González ◽  
Carmen Carneiro ◽  
Vanesa Santos ◽  
Erea Borrajo ◽  
Blanca Dominguez ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Residual Disease ◽  
Water Soluble ◽  
Molecular Cluster ◽  
Medical Need ◽  
Wide Range ◽  
Hematological Cancers

[Background on medical need in hematology]Even though significant progress has been made in a number of hematological malignancies in recent years, an unmet medical need still remains in indications such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML) due to refractory disease, severe adverse events or the failure to achieve sustained minimal residual disease. As a consequence, novel therapies are required to prevent relapse, be safer in administration and to target residual disease. We present here for the first time a novel and innovative therapeutic approach with the potential to treat patients suffering from hard-to-treat hematological malignancies based on the tumor´s pathophysiology and reactive oxygen species (ROS) phenotype. [Background on Ag5]TMC are created by combining the atoms of certain transition metals under specific conditions to form novel molecules with entirely distinct properties from "traditional" metal. For example, silver can be used to create clusters of different and defined sizes, based on the number of atoms making up the final drug candidate. More specifically, Ag5 contains five silver atoms arranged in a specific conformation, is the first TMC derived from this novel platform and has entirely different physiological properties than the three silver atom containing Ag3. Ag5 is a water-soluble and heat stable molecule, it is orally bioavailable and a freely diffusible pan-tumor therapeutic. It selectively kills those cells with high ROS concentrations by oxidizing their antioxidant systems and subsequently drives these cells to programmed cell death. In consequence, Ag5 will preferentially kill cancer cells which typically have higher ROS levels, but will spare normal cells which display lower ROS due to their functional REDOX homeostasis. More specifically, Ag5 efficiently catalyzes the oxidation of thiol groups of thioredoxins and peroxiredoxins and thereby drives sensitive cells above a threshold to irreversible protein misfolding, protein degradation and programmed cell death. [Background on Ag5 experiments]We characterized Ag5 efficacy using a wide range ofin vitroassays and found potent Ag5 efficacy against a number of MM, CLL and AML cell lines with an IC50 in the low nM range. Ag5 sensitivity of all cell lines was correlated with ROS levels, more specifically superoxide, as measured by dihydroethidium (DHE) or MitoSOX. Furthermore, we were able to demonstrate that Ag5 treatment resulted in a concentration dependent cell cycle arrest in G1 phase, mitochondrial swelling and induction of apoptosis. Treatment of primary CLL tumor samples resulted in low nM efficacy. Finally, we could demonstrate that Ag5 was not only safely administered without any side effects in mouse and rat studies, but was equally effective as the stand-of-care bortezomib in a multiple myelomain vivomodel. [Conclusion and clinical significance]In summary, Ag5 is a novel and innovative therapeutic candidate that was shown to be safe and effective in preclinical studies, and has the promise to address the unmet medical need in hard-to-treat hematological malignancies. Keywords: Ag5, Therapeutic molecular cluster (TMC), Redox, ROS, catalysis, Ag3, AML, MM, CLL Disclosures Porto González: Arjuna:Research Funding.Carneiro:Arjuna:Research Funding.Lopez-Quintela:Arjuna:Current equity holder in private company.Treder:Arjuna:Current Employment.Dominguez:Arjuna:Current equity holder in private company.

scholarly journals Cytotoxic Effects of Pinnatane A Extracted from Walsura pinnata (Meliaceae) on Human Liver Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2733 ◽  
Author(s):  
Nurhisyam Zakaria ◽  
Mohamad Mahdzir ◽  
Mahfuzah Yusoff ◽  
Norhafiza Mohd Arshad ◽  
Khalijah Awang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Death ◽  
Liver Cancer ◽  
Cell Lines ◽  
Human Liver ◽  
Annexin V ◽  
Normal Cells ◽  
Cycle Arrest ◽  
Anti Cancer

Background: Pinnatane A from the bark of Walsura pinnata was investigated for its anti-cancer properties by analyzing the cytotoxic activities and cell cycle arrest mechanism induced in two different liver cancer cell lines. Methods: A 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to analyze the pinnatane A selectivity in inducing cell death in cancer and normal cells. Various biological assays were carried out to analyze the anti-cancer properties of pinnatane A, such as a live/dead assay for cell death microscopic visualization, cell cycle analysis using propidium iodide (PI) to identify the cell cycle arrest phase, annexin V-fluorescein isothiocyanate (annexin V-FITC)/PI flow cytometry assay to measure percentage of cell populations at different stages of apoptosis and necrosis, and DNA fragmentation assay to verify the late stage of apoptosis. Results: The MTT assay identified pinnatane A prominent dose- and time-dependent cytotoxicity effects in Hep3B and HepG2 cells, with minimal effect on normal cells. The live/dead assay showed significant cell death, while cell cycle analysis showed arrest at the G0/G1 phase in both cell lines. Annexin V-FITC/PI flow cytometry and DNA fragmentation assays identified apoptotic cell death in Hep3B and necrotic cell death in HepG2 cell lines. Conclusions: Pinnatane A has the potential for further development as a chemotherapeutic agent prominently against human liver cells.

Synthesis, Spectral Characterization, Antibacterial and Anticancer Activity of some Titanium Complexes

2018 ◽  
Vol 18 (5) ◽  
pp. 739-746 ◽  
Author(s):  
Raj Kaushal ◽  
Nitesh Kumar ◽  
Archana Thakur ◽  
Kiran Nehra ◽  
Pamita Awasthi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Spectral Characterization ◽  
Mechanistic Study ◽  
Titanium Complexes ◽  
G0 Phase ◽  
Antibacterial And Anticancer Activity ◽  
Dose Dependent

Abstract: Background: After the discovery of cisplatin, first non platinum anticancer drugs having excellent efficacy were budotitane and TiCl2(cp)2 but action mechanism is not clear. Therefore, we hereby reporting synthesis and biological activities novel titanium complexes to explore their mode of action. Objectives: Synthesis, spectral characterization, antibacterial and anticancer activity of some titanium complexes. Antibacterial studies on various bacterial strains and anticancer studies on HeLa, C6, CHO cancerous cell lines have been performed. Further, the cell death mechanistic study was done on CHO cell lines. Method: Titanium complexes with and without labile groups have been synthesized by reacting of TiCl4 with nitrogen containing ligands viz. 1,2-diaminocyclohexane, 1,10-Phenanthroline, adamantylamine, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine in predetermined molar ratios. Antibacterial and anticancer studies were performed by agar well diffusion method and MTT assay respectively. Cell cycle analysis is done by using flow cytometry. Results: Complex 2 i.e TiCl2(Phen)2 showed better activity than other complexes as an antibacterial as well as anticancer agent. Phase contrast imaging indicates that observed morphological changes of cells was dose dependent. Cell death mechanistic study have shown the increase in sub G0 phase population as well as formation of blebbing and fragmentation of chromatin material which is an indicative measure of apoptosis. Conclusion: Complex 2 proved to be more effective bactericide and cytotoxic agent. Cell cycle analysis showed cell arrest in G0 phase. Apoptosis percentage was found to increase in a dose dependent manner. So, prepared titanium complexes can be put to use as an important chemotherapeutic agents.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

2019 ◽  
Vol 19 (5) ◽  
pp. 599-609 ◽  
Author(s):  
Sumathi Sundaravadivelu ◽  
Sonia K. Raj ◽  
Banupriya S. Kumar ◽  
Poornima Arumugamand ◽  
Padma P. Ragunathan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Black Cumin ◽  
In Silico Docking ◽  
Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

Antitumor Effect of Pomolic Acid in Acute Myeloid Leukemia Cells Involves Cell Death, Decreased Cell Growth and Topoisomerases Inhibition

2019 ◽  
Vol 18 (10) ◽  
pp. 1457-1468
Author(s):  
Michelle X.G. Pereira ◽  
Amanda S.O. Hammes ◽  
Flavia C. Vasconcelos ◽  
Aline R. Pozzo ◽  
Thaís H. Pereira ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Natural Compound ◽  
Dna Topoisomerases ◽  
Human Dna ◽  
Pomolic Acid ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) represents the largest number of annual deaths from hematologic malignancy. In the United States, it was estimated that 21.380 individuals would be diagnosed with AML and 49.5% of patients would die in 2017. Therefore, the search for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. Objectives: To investigate the cytotoxicity effect of the natural compound pomolic acid (PA) and to explore the mechanism of action of PA in AML cell lines with different phenotypes. Methods: Three different AML cell lines, HL60, U937 and Kasumi-1 cells with different mechanisms of resistance were used to analyze the effect of PA on the cell cycle progression, on DNA intercalation and on human DNA topoisomerases (hTopo I and IIα) in vitro studies. Theoretical experiments of the inhibition of hTopo I and IIα were done to explore the binding modes of PA. Results: PA reduced cell viability, induced cell death, increased sub-G0/G1 accumulation and activated caspases pathway in all cell lines, altered the cell cycle distribution and inhibited the catalytic activity of both human DNA topoisomerases. Conclusion: Finally, this study showed that PA has powerful antitumor activity against AML cells, suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.

scholarly journals SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalyan Mahapatra ◽  
Sujit Roy
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Salinity Stress ◽  
Crucial Role ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

scholarly journals Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 925
Author(s):  
Eva-Maria Faulhaber ◽  
Tina Jost ◽  
Julia Symank ◽  
Julian Scheper ◽  
Felix Bürkel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Side Effects ◽  
Ionizing Radiation ◽  
Cell Lines ◽  
Normal Tissue ◽  
Kinase Inhibitors ◽  
Induced Response ◽  
Tumor Control ◽  
Tumor Cell Death

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

Simvastatin Induces Death of Multiple Myeloma Cell Lines

2004 ◽  
Vol 52 (5) ◽  
pp. 335-344 ◽  
Author(s):  
Naomi Gronich ◽  
Liat Drucker ◽  
Hava Shapiro ◽  
Judith Radnay ◽  
Shai Yarkoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Cytoplasmic Calcium ◽  
Multiple Myeloma Cell ◽  
Cycle Arrest ◽  
Rpmi 8226

BackgroundAccumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.MethodsU266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 μM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.ResultsExposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 μM for ARH77, 8 μM for RPMI 8226, and 13 μM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.ConclusionsSimvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.

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