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 Genistein Derivatives Regioisomerically Substituted at 7-O- and 4′-O- Have Different Effect on the Cell Cycle

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
A. Byczek ◽  
J. Zawisza-Puchalka ◽  
A. Gruca ◽  
K. Papaj ◽  
G. Grynkiewicz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Biological Effects ◽  
Cancer Cell Lines ◽  
Dna Lesions ◽  
Hydroxyl Group ◽  
Human Cancer Cell Lines

Our previous studies on antiproliferative properties of genistein derivatives substituted at C7 hydroxyl group of the ring A revealed some compounds with antimitotic properties. The aim of this work was to synthesize their analogues substituted at the 4′-position of the ring B in genistein and to define their antiproliferative mechanism of action in selected cancer cell linesin vitro. C4′-substituted glycoconjugates were obtained in a three-step procedure: (1) alkylation with anω-bromoester; (2) deacylation; (3) Ferrier-type rearrangement glycosylation with acylated glycals. Biological effects including antiproliferative effects of the compounds, cell cycle, DNA lesions (ATM activation, H2A.X phosphorylation, and micronuclei formation), and autophagy were studied in human cancer cell lines. Some of the tested derivatives potently inhibited cell proliferation. The presence of a substituent at the 4′-position of the ring B in genistein correlated to a p53-independent G1 cell-cycle arrest. The derivatives substituted at C4′ did not induce DNA lesions and appeared to be nongenotoxic. The tested compounds induced autophagy and caused remarkable decrease of cell volume.

Effect of p-PAQR3Thr32 on PD-L1 expression and immune evasion in gastric cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15571-e15571
Author(s):  
Zhi-Qiang Ling
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Cancer Cell Lines ◽  
Expression Level ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines

e15571 Background: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in some solid tumors. We have now examined PD-L1 expression and its regulation in gastric cancer with p-PAQR3Thr32 protein. Methods: The expression of PD-L1 at the protein and mRNA levels in gastric cancer cell lines was examined by flow cytometry, real-time RT-PCR and western blot analysis, respectively. The expression of PD-L1 and p-PAQR3Thr32 protein in 319 surgically resected gastric cancer specimens was evaluated by immunohistochemical analysis. Results: The PD-L1 expression level was higher in gastric cancer cell lines positive for p-PAQR3Thr32 protein induced by glucose starvation than in those negative for the p-PAQR3Thr32 protein. Forced expression of p-PAQR3Thr32 protein in gastric cancer cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in p-PAQR3Thr32 protein positive gastric cancer cells was attenuated by treatment with PAQR3 siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the IRF1 and STAT1 in IFNs-PDL1 signaling pathway in gastric cancer cells positive for p-PAQR3Thr32 protein. At clinical tissue level, the expression level of PD-L1 was positively associated with the presence of p-PAQR3Thr32 protein in gastric cancer specimens. Moreover, the expression level of p-PAQR3Thr32 protein was negatively correlated with CD3, CD8, GZMA (CD8 T cell secretory factor) and positively correlated with CD68 (macrophage marker). Conclusions: Our findings that p-PAQR3Thr32 protein induced by glucose deficiency upregulate PD-L1 by activating IFNs-PDL1 signaling pathway in gastric cancer reveal a direct link between p-PAQR3Thr32 protein and PD-L1 expression. It is suggested that p-PAQR3Thr32 protein may be involved in tumor immunosuppression by inhibiting the proliferation and activity of CD8 T cells in gastric cancer tissues.

scholarly journals Secondary Metabolites of Saussurea costus Leaf Extract Induce Apoptosis in Breast, Liver, and Colon Cancer Cells by Caspase-3-Dependent Intrinsic Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ali A. Shati ◽  
Mohammed A. Alkahtani ◽  
Mohamed Y. Alfaifi ◽  
Serag Eldin I. Elbehairi ◽  
Fahmy G. Elsaid ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agent ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Expression Level ◽  
Intrinsic Pathway ◽  
Anticancer Effect

Background. Apoptosis, a major form of programmed cell death, plays a vital role in regulating tissue development and maintenance of homeostasis in eukaryotes. Apoptosis can occur via a death receptor-dependent extrinsic or a mitochondrial-dependent intrinsic pathway and can be induced by various chemotherapeutic agents. In this study, the anticancer activity of Saussurea costus and its mode of intervention in human cancer cells of breast, colon, and liver were investigated. Results. In this study, the bioactives of S. costus leaves were extensively extracted in five solvents of different polarity. The cytotoxicity and anticancer effect of the extracted secondary metabolites were investigated against breast (MCF-7), liver (HepG2), and colon (HCT116) cancer cell lines using a Sulphorhodamine B (SRB) assay. Secondary metabolites extracted using hexane, methanol, ethyl acetate, and chloroform had the highest cytotoxicity and thus the greatest anticancer effect on all the cancer cell lines tested (IC50; ranging from 0.25 to 2.5 μg/ml), while butanol was comparatively less active (IC50; ranging from 23.2 to 25.5 μg/ml). Further investigation using DNA flow cytometry and fluorescent microscopy revealed that the extract arrested the cells in the G1 phase of cell cycle and induced apoptosis. Furthermore, the elevated expression level of proapoptotic proteins and decreased expression level of antiapoptotic proteins confirmed that the intrinsic (mitochondrial) pathway was involved in mediating the apoptosis of cancer cells upon treatment with S. costus extract. These results altogether suggest that S. costus could be a potential anticancer agent. Conclusion. These results suggest that the S. costus extract is the potential source of the secondary metabolites that could be used as anticancer agent to treat diverse cancers of breast, colon, and liver.

scholarly journals The Mechanism of miR-141 Regulating the Proliferation and Metastasis of Liver Cancer Cells by Targeting STAT4

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lili Ma ◽  
Hui Shao ◽  
Huazhong Chen ◽  
Qilong Deng
Keyword(s):  
Cell Proliferation ◽  
Liver Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Expression Level ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Liver Cancer Cell ◽  
Qrt Pcr

Background. In recent years, it has been reported that miRNA can be used as one of the markers of tumor diagnosis, treatment, and prognosis (including liver cancer), and it plays an important role in tumorigenesis. However, there are still very few studies on the mechanism and role of miR-141 in liver cancer. Methods. qRT-PCR was used to test the expressions of miR-141 and STAT4 in collected liver cancer tissues and adjacent tissues, cultured liver cancer cell lines MHCC97H, Hep3B, and Huh7, and normal human liver cells HL7702. After processing the results of the qRT-PCR experiment, liver cancer cell MHCC97H which has the lowest expression level was decided to be taken as the research object. miR-NC, miR-141 mimics, si-NC, si-STAT4, miR-141 mimics and pcDNA-NC, and miR-141 mimics and pcDNA-STAT4 were transfected into MHCC97H cells, respectively. The MTT assay was used to detect the proliferation of each group of cells, and the Transwell test was used to detect the effect of miR-141 on cell proliferation, migration, and invasion. The interaction between miR-141 and STAT4 was verified by the dual-luciferase reporter experiment, and the expression level of Cyclin D1 and MMP2 was detected by the western blot. Results. Compared with normal cell HL7702, the expression level of miR-141 in liver cancer cell lines was relatively low P < 0.05 and the expression level of STAT4 in liver cancer cell lines was relatively high P < 0.05 after testing the expression level of STAT4; transfecting miR-141 mimics or Si-SLBP can inhibit cell proliferation, migration, and invasion; dual-luciferase reporter experiments confirmed that miR-141 can specifically bind to the 3′UTR of STAT4; cotransfection of miR-141 mimics and pcDNA-STAT4 can antagonize the effects of miR-141 mimics on cell proliferation, migration, and invasion. Conclusion. miR-141 can target the STAT4 gene expression to inhibit the proliferation, migration, and invasion of liver cancer cells.

scholarly journals GHRH-R Expression Level under Hyperglycaemic Like Culture Conditions in Breast Cancer Cell Lines

2017 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara Hesham Amer Awad ◽  
Mira Emad ElDin Abd El Aal Mohammed Ibrahim ◽  
Gazala Afreen Khan ◽  
Samrein BM Ahmed
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Culture Conditions ◽  
Expression Level ◽  
Breast Cancer Cell Lines
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