Current Cancer Drug Targets - Volume 21, Issue 5, 2021

N6-methyladenosine (m⁶A) modifications control multifaceted RNA metabolism and are one of the most extensively distributed modifications on the human transcriptome, including non-coding RNAs (ncRNAs). Previous concepts of ncRNAs as “junk” transcriptional products have evolved to the concept that ncRNAs are functional regulatory molecules that determine specific biological processes and cell fates. The dysregulation of m⁶A modifications and ncRNAs have been implicated in the development of human carcinogenesis. Certain types of ncRNAs have been reported to exert regulatory effects on m⁶A machinery. However, a better understanding of the relationship between m⁶A modifications and ncRNAs in cancer is still needed. This review discusses mutual interactions between m⁶A modifications and ncRNAs and their impacts on the development of human cancer. We summarize the clinical significance of m⁶A-ncRNA networks for cancer diagnosis and treatment, and we ask challenging questions that remain unanswered in this field of research. Understanding the complex coordination between m⁶A modifications and ncRNAs will be useful for guiding the development of therapeutic interventions.

Head and neck squamous cell carcinoma (HNSCC) continues to be a global public health burden even after a tremendous development in its treatment. It is a heterogeneous cancer of upper aero-digestive tract. The contemporary strategy to treat cancer is the use of anticancer drugs against proteins possessing abnormal expression. Targeted chemotherapy was found successful in HNSCC, but, there is still a stagnant improvement in the survival rates and high recurrence rates due to undesirable chemotherapy reactions, non-specificity of drugs, resistance against drugs and drug toxicity on non-cancerous tissues and cells. Various extensive studies lead to the identification of drug targets capable to treat HNSCC effectively. The current review article gives an insight into these promising anticancer targets along with knowledge of drugs under various phases of development. In addition, new potential targets that are not yet explored against HNSCC are also described. We believe that exploring and developing drugs against these targets might prove beneficial in treating HNSCC.

The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents mitotic exit at the metaphase-to-anaphase transition until all chromosomes have established correct bipolar attachment to spindle microtubules. Activation of SAC relies on the assembly of the mitotic checkpoint complex (MCC), which requires conformational change from inactive open Mad2 (OMad2) to the active closed Mad2 (C-Mad2) at unattached kinetochores. The Mad2-binding protein p31^comet plays a key role in controlling timely mitotic exit by promoting SAC silencing, through preventing Mad2 activation and promoting MCC disassembly. Besides, increasing evidences highlight the p31^comet potential as target for cancer therapy. Here, we provide an updated overview of the functional significance of p31^comet in mitotic progression, and discuss the potential of deregulated expression of p31^comet in cancer and in therapeutic strategies.

Long non-coding RNAs (LncRNAs) epitomize a class of non-coding regulatory RNAs with more than 200 nucleotides, which are long and situated in the nucleus or cytoplasm and rarely encode proteins. Accruing evidence signposts that lncRNAs act as molecular switches in different cellular activities like differentiation, apoptosis, as well as reprogramming of cellular states by modifying gene expression patterns. The revelation of immense numbers of lncRNA with their wide variety of expression patterns in different kinds of malignancy, tumor explicitness, and their steadiness in circulating body fluids deliver an innovative groundwork for emerging diagnosis and treatments for cancer. Mechanisms associating lncRNAs in carcinogenesis are conquered by deregulation of cellular signaling pathways and altered epitranscriptome along with their expression. Specified these attributes, it becomes clear that the improvement of new tools to identify lncRNAs with higher affectability will be fundamental to allow the identification of the expression pattern of lncRNAs in various kinds of malignant growth and may likewise be utilized to envisage cancer prognosis in addition to the patients' outcome. Improvement of RNA targeting-based therapeutics is delivering incredible prospects to modulate lncRNAs for anti-cancer initiatives. Henceforth, lncRNAs can be used exclusively as possible cancer biomarkers for early diagnosis and anticipation of malignancy, as well as metastasis. In addition to the basic curative targets and along these, lncRNAs hold resilient assurance towards the revelation of innovative diagnostics and therapeutics for malignant growth with the interface of epitranscriptomics information. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis, regulation, and lncRNA-associated epigenetics of cancer along with targeting lncRNAs with potential approaches for impending diagnosis and therapeutic intervention in malignancies.

Background: A higher incidence of COVID-19 infection was demonstrated in cancer patients, including lung cancer patients. This study was conducted to get insights into the enhanced frequency of COVID-19 infection in cancer. Methods: Using different bioinformatics tools, the expression and methylation patterns of ACE2 and TMPRSS2 were analyzed in healthy and malignant tissues, focusing on lung adenocarcinoma and data were correlated to clinical parameters and smoking history. Results: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression levels in digestive, urinary and reproductive organs, while the overall analysis of 72 paired tissues demonstrated significantly lower expression levels of ACE2 in cancer tissues when compared to normal counterparts. In contrast, ACE2, but not TMPRSS2, was overexpressed in LUAD, which inversely correlated to the promoter methylation. This upregulation of ACE2 was age-dependent in LUAD, but not in normal lung tissues. TMPRSS2 expression in non-neoplastic lung tissues was heterogeneous and dependent on sex and smoking history, while it was downregulated in LUAD of smokers. Cancer progression was associated with a decreased TMPRSS2 but unaltered ACE2. In contrast, ACE2 and TMPRSS2 of lung metastases derived from different cancer subtypes was higher than organ metastases of other sites. TMPRSS2, but not ACE2, was associated with LUAD patients’ survival. Conclusions: Comprehensive molecular analyses revealed a heterogeneous and distinct expression and/or methylation profile of ACE2 and TMPRSS2 in healthy lung vs. LUAD tissues across sex, age and smoking history and might have implications for COVID-19 disease.

Background: Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron in cancer, iron chelation has been investigated for its antineoplastic properties in many tumors. Deferasirox is the most used iron chelator compound and in previous studies showed an anticancer effect in hematologic and solid malignancies. Eltrombopag is a Thrombopoietin receptor used in thrombocytopenia that also binds and mobilize iron. It demonstrated an effect on iron overload conditions and also in contrasting cancer cell proliferation. Objective: We analyzed the effects of deferasirox and eltrombopag in human osteosarcoma cells in an attempt to identify other therapeutic approaches for this tumor. Methods: We cultured and treated with deferasirox and Eltrombopag, alone and in combination, two human osteosarcoma cell lines, MG63 and 143B. After 72h exposure, we performed RTqPCR, Western Blotting, Iron Assay and cytofluorimetric assays to evaluate the effect on viability, apoptosis, cell cycle progression and ROS production. Results: The iron-chelating properties of the two compounds are also confirmed in osteosarcoma, but we did not observe any direct effect on tumor progression. Discussion: We tested deferasirox and eltrombopag, alone and in combination, in human osteosarcoma cells for the first time and demonstrated that their iron-chelating activity does not influence biochemical pathways related to cancer progression and maintenance. Conclusion: Although further investigations on possible effects mediated by cells of the tumor microenvironment could be of great interest, in vitro iron chelation in osteosarcoma does not impair tumor progression.