Highlight
Chemotherapeutic drugs are classified into alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and corticosteroids.
Most of the chemotherapeutic drugs act in a dose-dependent manner; they either stimulate apoptosis or chemoresistance.
Two major complications during chemotherapy are chemoresistance and tumor relapse. We have discussed underlying intracellular signaling cascades responsible for these events.
Combination chemotherapies, targeted therapies, and immunotherapies have represented more promising responses than single chemotherapy applications.
The role of omics, next-generation sequencing (NGS), whole-exome sequencing (WES), and machine learning technologies in precision medicine are currently under investigations for overcoming chemoresistance and tumor relapse.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of 80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.
Introduction
Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder described as a malignant blood disorder by accounts for 15–20% of all adult leukemia. MicroRNAs (miRNAs) play an important role in post-transcriptional regulation of gene expressions. Expression level of tumor suppressor-miRNAs, described as miRNAs that target the oncogens, can contribute to diagnosis and prognosis of some malignant disorders including CML. We theorized that according to the excessive proliferation and alteration in miRNA expressions, there could be a change in the expression of miRNAs in plasma carried by exosomes.
Methods
We consequently decided to detect the differences between normal and aberrant miRNA expression in human plasma sample to find out the possibility of diagnosis by these alterations. The expression of candidate miRNAs were compared using RNA extracted from the plasma of 50 patients, as well as 30 healthy individuals. We analysed the plasma miR-16-1, miR-20, miR-106, miR-126, miR-155, miR-222, and miR-451 expression levels in CML patients by individual real-time quantitative RT-PCR.
Results
All selected miRNAs were found to be upregulated in newly diagnosed CML patients compared to the control, while upregulation of only three (miR-20, 106 and 222) were significant (17.4, 19 and 74.95 fold change, respectively;
p
<0.0001).
In conclusion
microRNAs have a potential use in treatment of CML, as they can target the genes involved in cell cycle, MAPK, growth inhibition, TGF beta, and p53 signaling pathways. Therefore, these miRNA signatures provide the basis for their utilization as biomarkers in CML.
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