Form In Cancer Cells Research Articles

Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death.

A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s ; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.

Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death

AbstractA multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co‐administration. The viability of CT26 cells co‐cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non‐treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co‐administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.

Crosstalk between hypoxic cellular micro-environment and the immune system: a potential therapeutic target for infectious diseases.

There are overwhelming reports on the promotional effect of hypoxia on the malignant behavior of various forms of cancer cells. This has been proposed and tested exhaustively in the light of cancer immunotherapy. However, there could be more interesting functions of a hypoxic cellular micro-environment than malignancy. There is a highly intricate crosstalk between hypoxia inducible factor (HIF), a transcriptional factor produced during hypoxia, and nuclear factor kappa B (NF-κB) which has been well characterized in various immune cell types. This important crosstalk shares common activating and inhibitory stimuli, regulators, and molecular targets. Impaired hydroxylase activity contributes to the activation of HIFs. Inflammatory ligands activate NF-κB activity, which leads to the expression of inflammatory and anti-apoptotic genes. The eventual sequelae of the interaction between these two molecular players in immune cells, either bolstering or abrogating functions, is largely cell-type dependent. Importantly, this holds promise for interesting therapeutic interventions against several infectious diseases, as some HIF agonists have helped prevent immune-related diseases. Hypoxia and inflammation are common features of infectious diseases. Here, we highlighted the role of this crosstalk in the light of functional immunity against infection and inflammation, with special focus on various innate and adaptive immune cells. Particularly, we discussed the bidirectional effects of this crosstalk in the regulation of immune responses by monocytes/macrophages, dendritic cells, neutrophils, B cells, and T cells. We believe an advanced understanding of the interplay between HIFs and NF-kB could reveal novel therapeutic targets for various infectious diseases with limited treatment options.

Therapeutic Benefit of Salvigenin Against Various forms of Human Disorders Including Cancerous Disorders: Medicinal Properties and Biological Application in the Modern Medicine

: Natural products have always been used in medicine for the discovery of new biological molecules against different types of human disorders. Crude drugs have been used in different systems of medicine, including Traditional Chinese Medicine and the Ayurvedic System of Medicine. From ancient time to this modern age, special emphasis has been given to the traditional knowledge of plants based products for the development of newer and better modern drugs. Traditional medicines are always better choices in the medicine and healthcare system by the people of developing countries for the treatment of human disorders. Polyphenolic compounds have been used in medicine due to their vast medicinal application and pharmacological activities. Flavonoidal class chemicals are the better examples of polyphenolic compounds, which have a 15- carbon skeleton chemical structure. Salvigenin is a pure flavonoid class phytochemical found to be present in the Salvia lachnocalyx, Salvia hydrangea and Plectranthus amboinicus and other medicinal plants and vegetables. Pharmacologically salvigenin has been found to have cytotoxic effects on various forms of cancer cells, such as colon adenocarcinoma, breast adenocarcinoma and glioblastoma. Further salvigenin has beneficial potential in the medicine for the treatment of diabetes and protects cells against oxidative stress. In order to know the therapeutic benefit of salvigenin in the medicine, here in the present study, all the scientific research data of salvigenin have been collected and analyzed for their biological significance in medicine. Extensive pharmacological investigation has been performed to know the better medicinal properties of the salvigenin in modern medicine. Analytical techniques used in the separation, isolation and identification of salvigenin have also been searched and presented in the present work. From the above-presented data, it was found that salvigenin has significant biological potential in medicine and could be used for the development of newer and better molecule or drugs against various forms of human disorders, including cancerous disorders.

SUV39H1 is a New Client Protein of Hsp90 Degradated by Chaetocin as a Novel C-Terminal Inhibitor of Hsp90.

Hsp90 is often overexpressed with activated form in cancer cells, and many key cellular proteins are dependent upon the Hsp90 machinery (these proteins are called “client protein”). Nowadays, more client proteins and more inhibitors of Hsp90 are being discovered. Chaetocin has been identified as an inhibitor of histone methyl transferase SUV39H1. Herein, we find that Chaetocin is an inhibitor of Hsp90 which binds to the C-terminal of Hsp90α. Chaetocin inhibited a variety of Hsp90 client proteins including AMl1-ETO and BCL-ABL, the mutant fusion-protein in the K562 and HL-60 cells. SUV39H1 mediates epigenetic events in the pathophysiology of hematopoietic disorders. We found that inhibition of Hsp90 by Chaetocin and 17-AAG had ability to induce degradation of SUV39H1 through proteasome pathway. In addition, SUV39H1 interacted with Hsp90 through co-chaperone HOP. These results suggest that SUV39H1 belongs to a client protein of Hsp90. Moreover, Chaetocin was able to induce cell differentiation in the two cells in the concentration range of Hsp90 inhibition. Altogether, our results demonstrate that SUV39H1 is a new client protein of Hsp90 degradated by Chaetocin as a novel C-terminal inhibitor of Hsp90. The study establishes a new relationship of Chaetocin and SUV39H1, and paves an avenue for exploring a new strategy to target SUV39H1 by inhibition of Hsp90 in leukemia.

Abstract 5083: BSCHL-2046, a lead chalcone derivative from a newly synthesized library, is a potent neddylation inhibitor against the growth of prostate cancer cell lines

Abstract Members of the chalcone family of molecules and their derivatives have been shown to inhibit various forms of cancer cells. In particular, Flavokawain A has been shown to inhibit prostate cancer cell lines. In order to capitalize on the bioactive nature of chalcone derivatives, we created a library of chalcone derivatives based on the scaffold of Flavokawain A but with an additional anti-cancer moiety. Here we have demonstrated that BSCHL-2046, the most potent member of the library, inhibits cell growth of prostate cancer cell lines including LNCaP, C4-2B, DU145, 22Rv1, and PC3 with IC50’s ranging from 0.44µM-7.5µM. BSCHL-2046 inhibited Ubc12 neddylation in an in vitro assay at an IC50 of 1.5µM and demonstrated complete inhibition at a concentration of 6µM. BSCHL-2046 also reduced Nedd-8 conjugations to both Cullin-1 and Ubc12 in vivo in DU145 cells. The inhibition of neddylation by BSCHL-2046 resulted in an increased expression of p27 and CDT-1. Using molecular modeling, BSCHL-2046 was predicted to bind directly to the Cullin-RING E3 ligase complex. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that BSCHL-2046 significantly decreased heat-induced protein degradation of E3 subunits, supporting BSCHL-2046 directly binding to the complex. Furthermore, BSCHL-2046 at a concentration of 500nM and 1.25µM displayed a 75% to complete inhibition of colony formation of C4-2B cells in soft agar. Taken together, these results demonstrate BSCHL-2046 and its structural analogs are potent neddylation inhibitors that deserve further investigation for the prevention and treatment of prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Matthew A. Tippin, Dong Jun Fu, Liankun Song, Victor Pham, Xaolin Zi. BSCHL-2046, a lead chalcone derivative from a newly synthesized library, is a potent neddylation inhibitor against the growth of prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5083.

Circulatory microrna in acute myocardial infarction: A candidate biomarker for forensic investigation

MicroRNAs (miRNAs) are small non-coding RNAs regulated a gene expression which associated to many diseases. As they contribute to diverse biological process and respond to various kinds of cellular stress, their utility as diagnostic biomarkers have recently been explored. miRNAs have been detected in various type of human tissues and were used as novel biomarkers in clinical investigation for example; ischemic stroke, acute myocardial infarction (AMI) and several forms of cancer cells. Recently, circulatory miRNA was proved that It could be a potential biomarker to determine a cause of death. In order to verify the ability of miRNA as a diagnosis tool, 3 candidate miRNAs (miR-133a, miR-208b and miR-499) associated to an early response of cardiac injury were selected. Twenty case-control cohorts using post-mortem blood samples were studied for miRNAs expression and post-mortem stability. The expression level of miR-499 was significantly increased in AMI groups compared to controls. The postmortem blood was in vitro tested during 12–18h which reveal a persistent of miRNAs in early decomposed environment.

Molecular Dynamics Simulations for Deciphering the Structural Basis of Recognition of Pre-let-7 miRNAs by LIN28.

LIN28 protein inhibits biogenesis of miRNAs belonging to the let-7 family by binding to precursor forms of miRNAs. Overexpression of LIN28 and low levels of let-7 miRNAs are associated with several forms of cancer cells. We have performed multiple explicit solvent molecular dynamics simulations ranging from 200 to 500 ns in length on different isoforms of preE-let-7 in complex with LIN28 and also in isolation to identify structural features and key specificity-determining residues (SDRs) that are important for the inhibitory role of LIN28. Our simulations suggest that a conserved structural feature of the loop regions of preE-let-7 miRNAs is more important for LIN28 recognition than sequence conservation among members of the let-7 family or the presence of the GGAG motif in the 3' region. The loop region consisting of a minimum of five nucleotides helps pre-miRNAs to acquire a conformation ideal for binding to LIN28, but pre-let-7c-2 prefers a conformation with a three-nucleotide loop. Thus, our simulations provide a theoretical rationale for the recent experimental observation of the escape of LIN28-mediated repression by pre-let-7c-2. The essential structural and sequence features highlighted in this study might aid in designing synthetic small molecule inhibitors for modulating LIN28-let-7 interaction in malignant cells. We have also identified crucial SDRs of the LIN28-preE-let-7 complex involving 13 residues of LIN28 and 10 residues of the pre-miRNA. On the basis of the conservation profile of these 13 SDRs, we have identified 10 novel proteins that are not annotated as LIN28 like but are similar in sequence, domain, or fold level to LIN28.

Personalised therapy for Pancreatic Cancer: Challenges and Opportunities

<p>Pancreatic Ductal Adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers. Early metastatic spread and failure of standard chemotherapeutics both contribute to this statistic. Over the last decade many other cancer types have benefited from the targeted therapy revolution in which signalling networks found to be altered in cancer cells are specifically targeted. Despite an ever-growing understanding of the mutation profiles in PDAC, the vast majority of these approaches have failed for this form of malignancy. Chemotherapy, which simply targets dividing cells, remains the most effective available treatment option alongside surgery. Although targeting a broad range of tyrosine kinase receptors with erlotinib has been shown to offer a modest improvement in the 5-year survival when combined with the pyrimidine-based chemotherapeutic gemcitabine; this suggests that targeted approaches may be of benefit in at least some patients. PDAC is characterised by a long genomic tail of potentially actionable mutations but each appearing in only a small number of patients, making it difficult to show a survival benefit of a targeted therapy in an unselected group of patients. Identifying specific subpopulations based on molecular characterisation of the tumour is particularly difficult in PDAC because of problems in biospecimen acquisition; only a small proportion of patients undergo surgery and the organ is difficult to biopsy due to its location. Furthermore, PDAC is characterised by cellular heterogeneity within primary tumours and their metastases, meaning that targeted therapies may have only a transient effect, killing dominant cellular populations but leaving behind potentially even more aggressive forms of cancer cells that have unidentified (and so unexploited) molecular targets. In this review, consideration is given to overcoming the barriers of personalised medicine specific to PDAC with the aim of improving the 5-year survival rates</p>

Abstract 4096: A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer

Abstract PIBF is a unique protein that is secreted by gamma/delta T cells and precipitously rises in the sera following progesterone (P) exposure. The 34 kDa protein protects the fetal semi-allograft from immune surveillance by reducing cytoxicity of natural killer (NK) cells by stabilizing perforin granules. The parent 90 kDa form occupies a centrosomal position close to BRCA-1. PIBF can be found in most rapidly dividing cells. One study found an over-expression of the mRNA for the PIBF protein in all 29 leukemia cell lines tested. The P receptor antagonist mifepristone was found to down-regulate PIBF protein. Mifepristone provided significant palliative benefit to a large variety of spontaneous murine and human cancers. P could also be responsible for converting the 90 kDa parent form to a 34-36 kDa split variant in the cytoplasm which may be the immunosuppressive form in cancer cells. Alternatively, some P-like secretion by the tumor could influence gamma/delta T cells in the tumor microenvironment to secrete PIBF and possibly spill over to the sera. The aim of this study was to determine if there is any increase in serum PIBF in women with gynecologic cancer as opposed to controls. Serum was obtained from women about to have surgery for gynecologic problems including malignant and benign disorders. The samples would then be measured for PIBF using a new non-commercial enzyme linked immunoabsorbent assay (ELISA) for PIBF and serum progesterone. The PIBF levels (ng/mL) from lowest to highest in women with various gynecologic cancers (in all cases serum progesterone (P) <2ng/mL) were 10.06, 17.35, 32.59, 35.62, 54,7, and 57.17. The average serum PIBF was 34.6 ng/mL. There were 3 women with benign gynecologic tumors and the serum PIBF was 14.76, 15.7, and 36.64 their average serum PIBF was 22.5 ng/mL). There were 2 women with no tumors having gynecologic surgery and their serum PIBF levels (ng/mL) were 9.56 and 35.27 (with an average of 22.4 ng/mL). At least for gynecologic cancers if PIBF is conferring immune protection it is more likely operating through its intracytoplasmic presence rather than working through sera levels. In women or men exposed to exogenous or endogenous P for just 6 days it is not unusual to see sera PIBF rise to 300 to >800ng/mL. Citation Format: Jerome H. Check, Mojirayo Sarumi, Ann DiAntonio, Krystal Hunter, Gunda Simpkins, Marie Duroseau. A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2014-4096

Conversion of cathepsin E to enzymatic unstable form in gastric cancer cells.

A new acid proteinase in human gastric cancer, named medium moving proteinase (Med.P), was found also in a gastric cancer transplanted into nude mouse. However, Med.P disappeared when the samples prepared from gastric cancer tissues were left for over 4 weeks at -80 degrees C, whereas the activity of cathepsin E (CE) increased. When these samples were reduced by dithiothreitol (DTT), Med.P appeared again and the CE activity decreased. These phenomena, revealed by electrophoretic analyses, indicated that Med.P is a monomeric form of CE (mono-CE). At weakly alkaline pH and after heating, mono-CE appeared to be more unstable than CE. These results indicated that CE assume an enzymatically unstable monomeric form in cancer cells.

Frequency domain studies of impedance characteristics of biological cells using micropipet technique. I. Erythrocyte

This study aims at precise measurement of the membrane capacity and its frequency dependence of small biological cells using the micropipet technique. The use of AC fields as an input signal enables the magnitude and phase angle of membrane impedance to be measured at various frequencies. The micropipet technique was applied to human erythrocyte, and passive membrane capacity and conductivity were determined between 4 Hz and 10 KHz. Membrane capacity thus determined changed from 1.05 to 0.73 microF/cm2 between 4 Hz and 10 KHz. In addition to the micropipet technique, we used suspension method between 50 KHz and 10 MHz for the purpose of supplementing the new method with the one which has been in use for many years. We obtained a membrane capacity of 0.65-0.8 microF/cm2 using this technique. These values agree with the capacitance obtained with the micropipet method. Although this paper discusses only human erythrocytes, the study has been performed with lymphocytes and various forms of cancer cells. This paper is the first of the series of reports on frequency domain studies of the impedance characteristics of various biological cells.