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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson’s disease, Alzheimer’s disease, and other age-related diseases. This review focuses on Zn’s roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.

Background Tumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Indeed, tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Molecularly targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti-cancer immune surveillance, with potentially detrimental or favorable outcomes. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Our study aimed to characterize the different populations of the immune system in patients with CML affected by their treatment. Methods Forty-one patients with CML [33 treated with TKIs and 8 with TKIs plus interferon (IFN)-α] and 20 controls were enrolled in the present study. Peripheral blood populations of the immune system [referred to as the overview of immune system (OVIS) panel, Treg cells and MDSCs] and PD-1 expression were evaluated by flow cytometry. The immunological profile was assessed using the mRNA Pan-Cancer Immune Profiling Panel and a NanoString nCounter FLEX platform. Results Patients receiving combination therapy (TKIs + IFN-α) had lower numbers of lymphocytes, particularly T cells [838/µL (95% CI 594–1182)] compared with healthy controls [1500/µL (95% CI 1207 – 1865), p = 0.017]. These patients also had a higher percentage of Treg (9.1%) and CD4 + PD-1 + cells (1.65%) compared with controls [Treg (6.1%) and CD4 + /PD-1 + (0.8%); p ≤ 0.05]. Moreover, patients treated with TKIs had more Mo-MDSCs (12.7%) whereas those treated with TKIs + IFN-α had more Gr-MDSC (21.3%) compared to controls [Mo-MDSC (11.4%) and Gr-MDSC (8.48%); p ≤ 0.05]. CD56 bright NK cells, a cell subset endowed with immune-regulatory properties, were increased in patients receiving TKIs plus IFN-α compared with those treated with TKIs alone. Interestingly, serum IL-21 was significantly lower in the TKIs plus IFN-α cohort. Within the group of patients treated with TKI monotherapy, we observed that individuals receiving 2nd generation TKIs had lower percentages of CD4 + Treg (3.63%) and Gr-MDSC (4.2%) compared to patients under imatinib treatment (CD4 + Treg 6.18% and Gr-MDSC 8.2%), but higher levels of PD-1-co-expressing CD4 + cells (1.92%). Conclusions Our results suggest that TKIs in combination with IFN-α may promote an enhanced immune suppressive state.

Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total antioxidant status (TAS) and higher levels of peroxides, nitric oxide, peroxides/TAS, and 8-hydroxy-2-deoxyguanosine compared with controls. These patients had higher 5-mC levels and lower 5-hmC/5-mC ratio and LINE-1 methylation and increased methylation frequency of at least one methylated gene. Peroxide levels and peroxide/TAS ratio were higher in patients with methylated genes than those without methylation and negatively correlated with LINE-1 methylation and positively with 5-mC levels. The 5-hmC/5-mC ratio was significantly associated with progression to acute leukemia and peroxide/TAS ratio with overall survival. This study points to a relationship between oxidative stress and DNA methylation, two common pathogenic mechanisms involved in MDS, and suggests the relevance of 5-hmC/5-mC and peroxide/TAS ratios as complementary prognostic biomarkers.

Breast cancer (BC) is a malignant neoplasia with the highest incidence and mortality rates in women worldwide. Currently, therapies include surgery, radiotherapy, and chemotherapy, including targeted therapies in some cases. However, treatments are often associated with serious adverse effects. Looking for new options in BC treatment, we evaluated the therapeutic potential of cold atmospheric plasma (CAP) in two cell lines (MCF7 and HCC1806) with distinct histological features. Apoptosis seemed to be the most prevalent type of death, as corroborated by several biochemical features, including phosphatidylserine exposure, the disruption of mitochondrial membrane potential, an increase in BAX/BCL2 ratio and procaspase 3 loss. Moreover, the accumulation of cells in the G2/M phase of the cell cycle points to the loss of replication ability and decreased survival. Despite reported toxic concentrations of peroxides in culture media exposed to plasma, intracellular peroxide concentration was overall decreased accompanying a reduction in GSH levels shortly after plasma exposure in both cell lines. In HCC1806, elevated nitric oxide (NO) concentration accompanied by reduced superoxide levels suggests that these cells are capable of converting plasma-derived nitrites into NO that competes with superoxide dismutase (SOD) for superoxide to form peroxinitrite. The concomitant inhibition of the antioxidative activity of cells during CAP treatment, particularly the inhibition of cytochrome c oxidase with sodium azide, synergistically increased plasma toxicity. Thus, this in vitro research enlightens the therapeutic potential of CAP in the treatment of breast cancer, elucidating its possible mechanisms of action.

Lung cancer (LC) ranks as the most prevalent and deadliest cause of cancer death worldwide. Treatment options include surgery, chemotherapy and/or radiotherapy, depending on LC staging, without specific highlight. The aim was to evaluate the effects of X-radiation in three LC cell lines. H69, A549 and H1299 cell lines were cultured and irradiated with 0.5–60 Gy of X-radiation. Cell survival was evaluated by clonogenic assay. Cell death and the role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cell cycle were analyzed by flow cytometry. Total and phosphorylated P53 were assessed by western blotting. Ionizing radiation decreases cell proliferation and viability in a dose-, time- and cell line-dependent manner, inducing cell death preferentially by apoptosis with cell cycle arrest. These results may be related to differences in P53 expression and oxidative stress response. The results obtained indicate that sensibility and/or resistance to radiation may be dependent on molecular LC characteristics which could influence response to radiotherapy and treatment success.

Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin is an HSP90 inhibitor with better pharmacokinetic properties and fewer side effects than other similar drugs, but its role in overcoming imatinib resistance is not yet clarified. This work studied the therapeutic potential of alvespimycin in imatinib-sensitive (K562) and imatinib-resistant (K562-RC and K562-RD) CML cell lines. Metabolic activity was determined by the resazurin assay. Cell death, caspase activity, mitochondrial membrane potential, and cell cycle were evaluated by means of flow cytometry. Cell death was also analyzed by optical microscopy. HSPs expression levels were assessed by western blotting. Alvespimycin reduced metabolic activity in a time-, dose-, and cell line-dependent manner. Resistant cells were more sensitive to alvespimycin with an IC50 of 31 nM for K562-RC and 44 nM for K562-RD, compared to 50 nM for K562. This drug induced apoptosis via the mitochondrial pathway. In K562 cells, alvespimycin induced cell cycle arrest in G0/G1. As a marker of HSP90 inhibition, a significant increase in HSP70 expression was observed. Our results suggest that alvespimycin might be a new therapeutic approach to CML treatment, even in cases of resistance to imatinib.

microRNAs (miRs) dysregulation have emerged as a crucial step in tumorigenesis, being related with cancer development, progression and response to treatment. In chronic myeloid leukaemia (CML), the resistance to tyrosine kinase inhibitors (TKI) is responsible for treatment failure and could be linked to changes in miRs expression. This work aimed to correlate the expression levels of 3 miRs, miR-21, miR-26b and miR-451, with response to TKI treatment in CML patients. miR-451 levels at diagnosis were significantly higher in patients with optimal response after 6 and 12 months of therapy. Conversely, patients without optimal response had highest levels of miR-21. miR-21 and miR-451 appear to be good biomarkers of response, able to predict optimal TKI responders (p < 0.05). Using the combined profile of both miRs, we create a predictive model of optimal response after one year of treatment. This study highlights the role of miR-21 and miR-451 expression levels at diagnosis in predicting which patients achieve the optimal response.

The deregulation of apoptosis is involved in the development of several pathologies, and recent evidence suggests that apoptosis may be involved in chronic pain, namely in neuropathic pain. Neuropathic pain is a chronic pain state caused by primary damage or dysfunction of the nervous system; however, the details of the molecular mechanisms have not yet been fully elucidated. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect signals released by injured tissues and respond to these damage signals. TRP channels are similar to the voltage-gated potassium channels or nucleotide-gated channels that participate in calcium and magnesium homeostasis. TRP channels allowing calcium to penetrate into nerve terminals can activate apoptosis, leading to nerve terminal destruction. Further, some TRPs are activated by acid and reactive oxygen species (ROS). ROS are mainly produced in the mitochondrial respiratory chain, and an increase in ROS production and/or a decrease in the antioxidant network may induce oxidative stress (OS). Depending on the OS levels, they can promote cellular proliferation and/or cell degeneration or death. Previous studies have indicated that proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play an important role in the peripheral mediation of neuropathic pain. This article aims to perform a review of the involvement of apoptosis in pain, particularly the role of OS and neuroinflammation, and the clinical relevance of this knowledge. The potential discovery of new biomarkers and therapeutic targets can result in the development of more effective and targeted drugs to treat chronic pain, namely neuropathic pain. Highlights: Oxidative stress and neuroinflammation can activate cell signaling pathways that can lead to nerve terminal destruction by apoptosis. These could constitute potential new pain biomarkers and targets for therapy in neuropathic pain.

The non-homologous end joining pathway is vital for repairing DNA double-strand breaks (DSB), with DNA-dependent protein kinase (DNA-PK) playing a critical role. Altered DNA damage response (DDR) in chronic (CML) and acute myeloid leukemia (AML) offers potential therapeutic opportunities. We studied the therapeutic potential of AZD-7648 (DNA-PK inhibitor) in CML and AML cell lines. This study used two CML (K-562 and LAMA-84) and five AML (HEL, HL-60, KG-1, NB-4, and THP-1) cell lines. DDR gene mutations were obtained from the COSMIC database. The copy number and methylation profile were evaluated using MS-MLPA and DDR genes, and telomere length using qPCR. p53 protein expression was assessed using Western Blot, chromosomal damage through cytokinesis-block micronucleus assay, and γH2AX levels and DSB repair kinetics using flow cytometry. Cell density and viability were analyzed using trypan blue assay after treatment with AZD-7648 in concentrations ranging from 10 to 200 µM. Cell death, cell cycle distribution, and cell proliferation rate were assessed using flow cytometry. The cells displayed different DNA baseline damage, DDR gene expressions, mutations, genetic/epigenetic changes, and p53 expression. Only HEL cells displayed inefficient DSB repair. The LAMA-84, HEL, and KG-1 cells were the most sensitive to AZD-7648, whereas HL-60 and K-562 showed a lower effect on density and viability. Besides the reduction in cell proliferation, AZD-7648 induced apoptosis, cell cycle arrest, and DNA damage. In conclusion, these results suggest that AZD-7648 holds promise as a potential therapy for myeloid leukemias, however, with variations in drug sensitivity among tested cell lines, thus supporting further investigation to identify the specific factors influencing sensitivity to this DNA-PK inhibitor.