Cancer immunotherapy represents a promising new era in cancer management due to the relatively high safety margins and selectivity, compared to the classical cancer chemotherapeutic agents. However, there is an imperative need to overcome tumor resistance in order to improve clinical outcomes and maximize the benefits of cancer immunotherapy. The interaction between the programmed cell death‐1 (PD‐1) receptor and its ligand PD‐L1 is a vital immune checkpoint that is often adopted by cancer cells to undergo immune evasion. PD‐1/PD‐L1 signaling is regulated at multiple levels through the crosstalk with other immune targets or relevant signaling partners involved in the cancer progression. Among the significant epigenetic players that are implicated in modulating the immune system are microRNAs (miRNAs). A complex system of these noncoding RNAs regulates the gene expression at the post‐transcriptional level and plays a significant role in the modulation of both innate and the adaptive immune systems. The expression profile of immune‐modulatory miRNAs might be useful as a predictive biomarker for the response and clinical outcomes in cancer immunotherapy. Therefore, in the current review, we highlighted the role of miRNAs in cancer immune evasion through a critical discussion of their impact on key immune checkpoints as well as the role of miRNAs in cancer progression and resistance.
Abbreviations: 5AZA, 5-aza-2 0 -deoxycytidine; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; DNMT, DNA methyltransferase; HAT, histone acetyl transferase; HDAC, histone deacetylase; NSCLC, non-small cell lung cancer; PBS, phosphate-buffered saline; SCLC, small-cell lung cancer; TSA, trichostatin A; 5mc, 5-methyl cytosine.Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/ novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 -4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.
The design and synthesis of a quality compound library containing a small number of skeletally diverse scaffolds, whose members rapidly deliver new chemical probes active against multiple phenotypes, is paramount in drug discovery. In this context, an efficient one-pot strategy for the synthesis of a mini library of sp 3 -enriched hexahydropyrido[2′,1′:2,3]imidazo[1,5-a]quinolinium and hexahydrothiazolo[2′,3′:2,3]imidazo[1,5-a]quinolinium architectures, is described. This new one-pot method features a combination of Sc(OTf) 3 -catalyzed [4 + 1]-cycloaddition with aza-Michael addition reactions. The cascade results in a rapid and diastereoselective formation of these scaffolds via desymmetrization of the oxidative dearomatization products of phenols. Phenotypic screening of the mini library against multiple drug-resistant bacteria and a panel of cancer cell lines identified potential antibacterial and anticancer lead drug candidates. Further investigation of the anticancer leads, indicated by their activity as tubulin-polymerization inhibitors, represents a promising approach for cancer therapy.
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