scholarly journals Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and suberoylanilide hydroxamic acid in lymphoma cell lines

2011 ◽  
Vol 53 (5) ◽  
pp. 973-981 ◽  
Author(s):  
Benigno C. Valdez ◽  
David Murray ◽  
Yago Nieto ◽  
Yang Li ◽  
Guiyun Wang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Hydroxamic Acid ◽  
Alkylating Agent ◽  
Nucleoside Analogs ◽  
Lymphoma Cell ◽  
Suberoylanilide Hydroxamic Acid ◽  
Synergistic Cytotoxicity ◽  
Dna Alkylating Agent

scholarly journals Synergistic Cytotoxicity of Gemcitabine, Clofarabine and Edelfosine (± DNA alkylating agent) in Lymphoma Cell Lines

2014 ◽  
Vol 20 (2) ◽  
pp. S164
Author(s):  
Ben C. Valdez ◽  
Axel Zander ◽  
Guiyun Song ◽  
David Murray ◽  
Yago Nieto ◽  
...  
Keyword(s):  
Cell Lines ◽  
Alkylating Agent ◽  
Lymphoma Cell ◽  
Synergistic Cytotoxicity ◽  
Dna Alkylating Agent

scholarly journals Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines

2012 ◽  
Vol 40 (10) ◽  
pp. 800-810 ◽  
Author(s):  
Benigno C. Valdez ◽  
Yago Nieto ◽  
David Murray ◽  
Yang Li ◽  
Guiyun Wang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Alkylating Agents ◽  
Nucleoside Analog ◽  
Lymphoma Cell ◽  
Epigenetic Modifiers ◽  
Synergistic Cytotoxicity

scholarly journals Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines

2011 ◽  
Vol 6 (1) ◽  
Author(s):  
Susanne Oertel ◽  
Markus Thiemann ◽  
Karsten Richter ◽  
Klaus-J Weber ◽  
Peter E Huber ◽  
...  
Keyword(s):  
Cell Lines ◽  
Hydroxamic Acid ◽  
Heavy Ion ◽  
Suberoylanilide Hydroxamic Acid ◽  
Sarcoma Cell ◽  
Heavy Ion Therapy ◽  
Ion Therapy

Treatment with the Anti-CD20 Antibody (B1) and Irradiation Result in Synergistic Cytotoxicity That Is Dependent on MAPK Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2508-2508
Author(s):  
Andrei Ivanov ◽  
Mark S. Cragg ◽  
Tim M. Illidge
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Clonogenic Survival ◽  
Lymphoma Cell ◽  
Non Hodgkin Lymphoma ◽  
Morphological Studies ◽  
Synergistic Cytotoxicity ◽  
New Treatment ◽  
Anti Cd20

Abstract Radioimmunotherapy using radiolabeled anti-CD20 antibodies (mAb) is an effective new treatment in non-Hodgkin lymphoma with high response rates. However, the molecular mechanisms behind these impressive clinical responses are poorly understood. To elucidate these mechanisms we studied the signaling events evoked in a panel of lymphoma cell lines following treatment with anti-CD20 mAb alone or in combination with irradiation. In all three lymphoma cell-lines tested a synergistic cytotoxic effect was observed when the anti-CD20 mAb B1 was combined with irradiation. The additive effect seen with B1 mAb and radiation was not observed with Rituximab and could be reversed with MEK inhibitors U0126 and PD98059 as well as siRNA targeting MEK1 or 2. Moreover, addition of U0126 reversed the decrease in clonogenic survival triggered by treatment with B1 and irradiation. To further probe the mechanism of this synergistic cell death we used cell lines over-expressing BCL2 or crmA, to block mitochondrial and death receptor pathways, respectively. Although BCL2 and crmA over-expression mediated protection against radiation alone, it had no impact on the increased cytotoxicity induced by B1+irradiation. Morphological studies revealed gross vacuolization of the cytoplasm, yet relatively well preserved nuclei in cells treated with B1+irradiation. Taken together our data indicate that activation of the MAPK cascade is an important factor that contributes to the synergistic effect of anti-CD20 (B1) antibody and irradiation and provides important new insights into how this treatment may work in the clinic.

scholarly journals The Positive Enantiomer of a Novel Chiral DNA Alkylating Agent Exhibits Nanomolar Potency in Hematologic Cancers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3991-3991
Author(s):  
Jianli Zhou ◽  
Neha Biyani ◽  
Umesh Kathad ◽  
Aditya Kulkarni ◽  
Joseph McDermott ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Alkylating Agent ◽  
Metabolic Activation ◽  
Cancer Cell Lines ◽  
Dna Lesions ◽  
Expression Level ◽  
Hematologic Cancer ◽  
Highly Correlated ◽  
Dna Alkylating Agent

Abstract LP-184, or (-)-hydroxyurea methylacylfulvene, is a potent DNA alkylating agent that effectively kills solid tumors. It belongs to the acylfulvene compound family known to induce DNA lesions repaired by the Transcription-Coupled Nucleotide Excision Repair (TC-NER) pathway. Here, we show that LP-284, the synthetic positive enantiomer of LP-184, exhibited the greatest and broadest hematologic cancer antiproliferative activities among the 6 acylfulvenes, including illudin S, illudin M, Irofulven (LP-100), the semisynthetic racemic LP-184, the synthetic negative enantiomer LP-184, and LP-284. The distinct pharmacological activities of LP-284 may be due to differences in metabolic activation, transport, or affinity to cellular macromolecules. To determine whether metabolic activation plays a role, we compared the correlation between the expression of Prostaglandin Reductase 1 (PTGR1), the NADPH-dependent oxidoreductase known to convert Irofulven into its active metabolite, and the IC50 of LP-184, Irofulven, and LP-284. We found that the expression level of PTGR1 is highly correlated with LP-184 (r=0.88, p=8.4e-20) and Irofulven (r=0.71, p=4.7e-10) sensitivity, but not with LP-284 (r=-0.01, p=0.93). We also found that the average expression level of PTGR1 is significantly lower in hematologic cancer cell lines (n=180) than in solid tumor cell lines (n=856), indicating the existence of an alternative LP-284 activator in hematologic cells. Next, we checked mutation status, RNA expression, protein expression, and DNA methylation of 489 oxidoreductases, but none of the enzymes was highly correlated with LP-284 activity. To further explore the potential clinical application of LP-284 in hematologic cancers, we conducted cell viability assays in 18 hematologic cancer cell lines and found that LP-284 exhibited nanomolar potency in acute lymphocytic leukemia (average IC50: 351 nM), chronic myeloid leukemia (average IC50: 360 nM), B-cell lymphoma (average IC50: 366 nM), and Multiple Myeloma (MM, IC50: 334 nM). We also investigated the therapeutic potential of LP-284 in combination with spironolactone in treating MM. Spironolactone, an FDA approved drug for hypertension, degrades one of the key TC-NER players ERCC3 in MM, which in turn makes cells more vulnerable to helix-distorting DNA lesions likely caused by LP-284. While Spironolactone alone didn't cause cytotoxicity to the MM cell line RPMI8226, it reduced LP-284 IC50 by 2.4 fold. Taken together, we have demonstrated the importance of stereochemistry in acylfulvene activity. LP-284, likely to be activated through a different route, is a unique and potent acylfulvene for hematologic cancers. Additionally, pharmacological inhibition of the TC-NER pathway greatly promoted LP-284 cytotoxicity. We hypothesize that LP-284 induces DNA lesions, which may be lethal to TC-NER deficient cells and may block transcription of short-lived fusion genes that are essential for cancer cell survival until repaired. Therefore, our discovery of the novel enantiomer LP-284 may provide a targeted therapy option for hematologic cancers with compromised DNA repair. Disclosures Zhou: Lantern Pharma: Current Employment. Biyani: Lantern Pharma: Current Employment. Kathad: Lantern Pharma: Current Employment, Current equity holder in publicly-traded company. Kulkarni: Lantern Pharma: Current Employment. McDermott: Lantern Pharma: Current Employment. Bhatia: Lantern Pharma: Current Employment.

scholarly journals Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines

2014 ◽  
Vol 4 (1) ◽  
pp. e171-e171 ◽  
Author(s):  
B C Valdez ◽  
A R Zander ◽  
G Song ◽  
D Murray ◽  
Y Nieto ◽  
...  
Keyword(s):  
Cell Lines ◽  
Lymphoma Cell ◽  
Synergistic Cytotoxicity

Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Gopikrishna Moku ◽  
Swathi Vangala ◽  
Venu Yakati ◽  
Chaitanya Chakravarthi Gali ◽  
Soumen Saha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Phenyl Ring ◽  
Hydroxamic Acid ◽  
Brdu Incorporation ◽  
Suberoylanilide Hydroxamic Acid ◽  
Cytotoxic Potential ◽  
Study Results ◽  
Ic50 Values ◽  
Phenyl Moiety

Background: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers. Aim: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents. Methods: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays. Results: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 µM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 µM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs. Conclusion: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.

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