Decytabine enhances cytotoxicity induced by oxaliplatin and 5-fluorouracil in the colorectal cancer cell line Colo-205

<p>Abstract</p> <p>Background</p> <p>DNA methylation is an epigenetic phenomenon known to play an important role in the development of cancers, including colorectal cancer (CRC). Aberrant methylation of promoter regions of genes is potentially reversible, and if methylation is important for cancer survival, demethylation should do the opposite. To test this we have addressed the hypothesis that DNA methyltransferase inhibitors (DNMTi), decytabine and zebularine, potentiate inhibitory effects of classical anti-CRC cytostatics, oxaliplatin and 5-fluorouracil (5-FU), on survival of CRC cells <it>in vitro</it>.</p> <p>Results</p> <p>Isobole and median effect analysis revealed that decytabine shows potent synergistic interaction with oxaliplatin and 5-FU and that this is probably not the class effect of DNMTi as zebularine shows strong antagonistic interaction with oxaliplatin. The synergistic combination treatment was also applied to the cultures to investigate their mechanisms of action. We have shown that combinations of decytabine with cytostatics produced dose-dependent growth inhibition and treatment-induced apoptosis.</p> <p>Conclusion</p> <p>The observed synergism between decytabine and cytostatics is most probably related to the augmented apoptotic signal and allowed for significant (both biologically and statistically) reduction of the cytotoxic doses of cytostatics used.</p

Left and right ventricular global longitudinal strain assessment together with biomarker evaluation may have a predictive and prognostic role in patients qualified for hematopoietic stem cell transplantation due to hematopoietic and lymphoid malignancies – a pilot study description

Abstract The hematopoietic stem cell transplantation (HSCT) procedure is considered a cardiovascular burden. This is due to the potentially cardiotoxic cytostatic agents used before and the risks associated with peri-transplant procedures. We designed a pilot study to determine the clinical utility of the new ST2 marker; furthermore, we routinely assessed cardiac parameters in HSCT recipients. Based on previous cardio-oncology experience in lung and prostate cancer, we can confirm the prognostic and predictive value of classic cardiac biomarkers and modern echocardiography parameters such as global longitudinal strain of the left and right ventricle. After conducting this pilot study we can create a predictive and prognostic model for patients undergoing HSCT. This will greatly enrich our clinical practice, especially in treating older people

Extracellular Vesicles in Multiple Myeloma—Cracking the Code to a Better Understanding of the Disease

Multiple myeloma (MM) is a plasma cell-derived malignancy that stands for around 1.5% of newly discovered cancer cases. Despite constantly improving treatment methods, the disease is incurable with over 13,000 deaths in the US and over 30,000 in Europe. Recent studies suggest that extracellular vesicles (EVs) might play a significant role in the pathogenesis and evolution of MM. Further investigation of their role could prove to be beneficial in establishing new therapies and hence, improve the prognosis of MM patients. What is more, EVs might serve as novel markers in diagnosing and monitoring the disease. Great advancements concerning the position of EVs in the pathophysiology of MM have recently been shown in research and in this review, we would like to delve into the still expanding state of knowledge

CRL4^CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future

Does molecular docking reveal alternative chemopreventive mechanism of activation of oxidoreductase by sulforaphane isothiocyanates?

International audienceIsothiocyanates (ITC) are well-known chemopreventive agents extracted from vegetables. This activity results from the activation of human oxidoreductase. In this letter, the uncompetitive activatory mechanism of ITC was investigated using docking and molecular dynamics simulations. This indicates that NAD(P)H:quinone oxidoreductase can efficiently improve enzyme-substrate recognition within the catalytic site if the ITC activator supports the interaction in the uncompetitive binding site

The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins’ expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p &lt; 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy