Effectiveness of COVID-19 vaccines and their challenges (Review).

At the end of 2019, a new disease recognized such as severe acute respiratory syndrome (SARS), was reported in Wuhan, China. This disease was caused by an unknown SARS coronavirus 2 (SARS-CoV-2); a virus is characterized by high infectivity among humans. In some cases, this disease can be asymptomatic, while in other cases can induce flu-like symptoms or acute respiratory distress syndrome, pneumonia and death. For this reason, the World Health Organization and Public Health Emergency of International Concern declared a pandemic status in January 2020. Currently, numerous countries have been involved in the development of effective vaccines to protect humans against SARS-CoV-2 infection. The present review will discuss the four vaccines, AZD1222 (AstraZeneca or Vaxzevria), Janssen (Ad26.COV2.S), Moderna/mRNA-1273 and BioNTech/Fosun/Pfizer BNT162b1, that are currently in use worldwide to understand their efficacy, but also evaluate the difficulties and challenges of vaccine development. Although several questions should be addressed regarding these vaccines, the current review will examine the viral elements used in the coronavirus-19 vaccine that can play a crucial role in inducing a strong immune response, as well as the different adverse effects that they can cause to individuals.

The evidence of toxic wastes dumping in Campania, Italy.

The region of Campania (particularly Naples and Caserta) were subjected to extensive illegal dumping operations of toxic and radioactive wastes since the 1980s. The highly toxic wastes (HTW) dumping operations that have taken place both along the coast and the hinterland, have extremely adverse effects on health, livelihoods and the future prospect of sustainable development of the local population. The toxic wastes dumping in Campania is real and it has compromised (irreversibly) the human health, natural environment, food security and the long-term development prospects of the affected population. To reverse this tragic trend, it is necessery the identification, isolation and reclamation of the polluted sites and full assessment of the nature and the scale of the polluting chemicals and other hazardous wastes. The purpose of this review is to contribute significantly to the available evidence of the long-running toxic waste dumping in Campania and its negative impact on the health of population.

The roles of microRNAs in the pathogenesis and drug resistance of chronic myelogenous leukemia (Review).

Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active BCR-ABL fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of BCR-ABL protein for the effective treatment of CML. However, the development of drug resistance, caused by different genetic mechanisms, is the major issue in the clinical application of TKIs. These mechanisms include changes in expression levels of microRNAs (miRNAs). miRNAs are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. In the present review, we highlight the roles of miRNAs both in the progression and chemotherapy-resistance of CML. Our understanding of these mechanisms may lead to the use of this knowledge not only in the treatment of patients with CML, but also in other type of cancers.

Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells.

Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet-Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib.

Signaling mechanisms of resistance to EGFR- and Anti-Angiogenic Inhibitors cancer.

Colorectal cancer is among four most common malignancies and the second leading cause of cancer death in the western world. Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. More recently, further improvements in survival have occurred due to the use of novel targeted therapies such EGFR Tyrosine Kinase Inibitors (EGFR-TKIs), EGFR monoclonal antibodies (EGFR-mAb), and VEGF antibodies. Despite the initial clinical efficacy of these inhibitors in such cancer, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target and another it is activation of alternative signaling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying EGFR- and VEGF-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

Sphingosine kinases signalling in carcinogenesis.

Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1-phosphate (S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic activation mechanisms of SphK1.

Bypass mechanisms of resistance to tyrosine kinase inhibition in chronic myelogenous leukaemia.

Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patients can now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significant proportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiple molecular mechanisms of resistance have been identified and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain. The second is activation of alternative molecules that maintain the signalling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

Modulation of telomerase activity, bTERT and c-Myc induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin during Bovine Herpesvirus 1 infection in MDBK cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) influences infection of kidney cells (MDBK) with Bovine Herpesvirus 1 (BHV-1) through an increase in virus replication and an acceleration of BHV-1-induced apoptosis. Previously our group demonstrated that BHV-1, in the early stages of infection, significantly up-regulates telomerase activity in MDBK cells, while, in the late phases of infection, when BHV-1-induced apoptosis occurred, a down-regulation of telomerase activity was detected. Hence, herein, for the first time, we described the influences of TCDD on telomerase activity during virus infection. In kidney cells (MDBK) infected with BHV-1 and exposed to different doses of TCDD we explored telomerase activity by TRAP assay. Concomitantly, we examined protein levels of both bTERT and c-Myc by Western blot analysis. In all groups, TCDD induced an acceleration in down-regulation of telomerase activity. Particularly, TCDD drastically and significantly decreased telomerase activity when virus-induced apoptosis took place. This result was accompanied from an accelerated down-regulation of bTERT and c-Myc. Finally, in the presence of TCDD, we evidenced a dose-dependent overexpression of aryl hydrocarbon receptor. Hence, our data suggest that TCDD, through a significant acceleration in down-regulation of telomerase activity, bTERT and c-Myc, may contribute to accelerated BHV-1-induced apoptosis.

SIRT1 silencing confers neuroprotection through IGF-1 pathway activation.

The following study demonstrated that, in in vitro differentiated neurons, SIRT1 silencing induced an increase of IGF-1 protein expression and secretion and of IGF-1R protein levels which, in turn, prolonged neuronal cell survival in presence of an apoptotic insult. On the contrary, SIRT1 overexpression increased cell death. In particular, IGF-1 and IGF-1R expression levels were negatively regulated by SIRT1. In SIRT1 silenced cells, the increase in IGF-1 and IGF-1R expression was associated to an increase in AKT and ERK1/2 phosphorylation. Moreover, neuronal differentiation was reduced in SIRT1 overexpressing cells and increased in SIRT1 silenced cells. We conclude that SIRT1 silenced neurons appear more committed to differentiation and more resistant to cell death through the activation of IGF-1 survival pathway.

Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models.

PURPOSE: Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat"-the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described. EXPERIMENTAL DESIGN: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients. RESULTS: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.

Blood-derived stem cells (BDSCs) plasticity: in vitro hepatic differentiation.

The limited availability of hepatic tissue suitable for the treatment of liver disease and drug research encourages the generation of hepatic-like cells from alternative sources as support for the regenerative medicine. Human blood derived stem cells (BDSCs) express surface markers and genes characteristic of pluripotent stem cells and have the ability to differentiate into different cell types, including tissues of endodermal origin (i.e., liver). Therefore they can represent a valuable source of hepatocytes for medicine. In this investigation, we exploited a fast hepatic differentiation protocol to generate hepatocyte-like cells from human BDSCs using only hepatocyte growth factor (HGF) and fibroblast growth factor-4 (FGF-4) as growth factors. The resulting cell population exhibited hepatic cell-like morphology and it was characterized with a variety of biological endpoint analyses. Here, we demonstrate how human BDSCs can be reprogrammed in hepatocyte-like cells by morphological, functional analysis, reverse transcriptase (RT)-PCR, and Western Blot assay. This study defines a fast and easy reprogramming strategy that facilitates the differentiation of human BDSCs along a hepatic lineage and provides a framework for a helpful source in the stem cells therapy and liver disorders.

Blood derived stem cells: an ameliorative therapy in veterinary ophthalmology.

Stem cell technology has evoked considerable excitement among people interested in the welfare of animals, as it has suggested the potential availability of new tools for several pathologies, including eye disease, which in many cases is considered incurable. One such example is ulcerative keratitis, which is very frequent in horses. Because some of these corneal ulcers can be very severe, progress rapidly and, therefore, can be a possible cause of vision loss, it is important to diagnose them at an early stage and administer an appropriate treatment, which can be medical, surgical, or a combination of both. The therapeutic strategy should eradicate the infection in order to reduce or stop destruction of the cornea. In addition, it should support the corneal structures and control the uveal reaction, and the pain associated with it, in order to minimize scarring. In this study, we address how stem cells derived from peripheral blood can be used also in ophthalmological pathologies. Our results demonstrate that this treatment protocol improved eye disease in four horse cases, including corneal ulcers and one case of retinal detachment. In all cases, we detected a decrease in the intense inflammatory reaction as well as the restoration of the epithelial surface of the central cornea.

Involvement of FOXO transcription factors, TRAIL-FasL/Fas, and sirtuin proteins family in canine coronavirus type II-induced apoptosis.

n our previous study, we have shown that canine coronavirus type II (CCoV-II) activates both extrinsic and intrinsic apoptotic pathway in a canine fibrosarcoma cell line (A-72 cells). Herein we investigated the role of Sirtuin and Forkhead box O (FOXO) families in this experimental model using Nortern Blot and Western Blot analysis. Our results demonstrated that mitochondrial SIRT3 and SIRT4 protein expression increased from 12 and 24 h post infection (p.i.) onwards, respectively, whereas the nuclear SIRT1 expression increased during the first 12 h p.i. followed by a decrease after 36 h p.i., reaching the same level of control at 48 h p.i. Sirtuins interact with/and regulate the activity of FOXO family proteins, and we herein observed that FOXO3A and FOXO1 expression increased significantly and stably from 12 h p.i. onwards. In addition, CCoV-II induces a remarkable increase in the expression of TNF-related apoptosis-inducing ligand (TRAIL), while we observed a slight up-regulation of FasL/Fas at 36 p.i. with a decrease of both proteins at the end of infection. Furthermore, we found that virus infection increased both bax translocation into mitochondria and decreased bcl-2 expression in cytosol in a time-dependent manner.These data suggest that FOXO transcription factors mediate pro-apoptotic effects of CCoV-II, in part due to activation of extrinsic apoptosis pathway, while some Sirtuin family members (such as SIRT3 and SIRT4) may be involved in intrinsic apoptotic pathway. Moreover, these results propose that TRAIL is an important mediator of cell death induced by CCoV-II during in vitro infection.

2,3,7,8-tetrachlorodibenzo-p-dioxin induced autophagy in a bovine kidney cell line.

The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to a variety of cultured cells may alter their ability to proliferate and die. In a previous study we demonstrated that TCDD induced proliferation in Madin-Darby Bovine Kidney (MDBK) cells where no signs of apoptosis were observed, but herein, analysis of MDBK cell morphology, in a large number of exposed cells, revealed some alterations, as expanded cytoplasm, an increase of intercellular spaces and many pyknotic nuclei. Hence, the aim of the current study was to elucidate the influences of dioxin on cell proliferation and cell death. We found that dioxin increased proliferation, as well as, activated cell death with autophagy, as we detected by increased amount of LC3-II, an autophagosome marker. Furthermore, formation of acidic vesicular organelles was observed by fluorescence microscopy following staining with the lysosomotropic agent acridine orange. These results were accompanied by down-regulation of telomerase activity, bTERT and c-Myc. Key tumor-suppressor protein p53 and expression of cell cycle inhibitor p21Waf1/Cip1 were activated after TCDD exposure. These changes occurred with activation of ATM phosphorylation in the presence of a decrease in Mdm2 protein levels. Taken together, these results support the idea that TCDD in MDBK cells, may exert its action, in part, by enhancing cell proliferation, but also by modulating the incidence of induced cell death with autophagy.

Hypoxia-increased RAGE and P2X7R expression regulates tumor cell invasion through phosphorylation of Erk1/2 and Akt and nuclear translocation of NF-{kappa}B.

The role of hypoxia in regulating tumor progression is still controversial. Here, we demonstrate that, similarly to what previously observed by us in human prostate and breast tumor samples, hypoxia increases expression of the receptor for advanced glycation end products (RAGE) and the purinergic receptor P2X7 (P2X7R). The role of hypoxia was shown by the fact that hypoxia-inducible factor (HIF)-1α silencing downregulated RAGE and P2X7R protein levels as well as nuclear factor-kappaB (NF-κB) expression. In contrast, NF-κB silencing reduced P2X7R expression without affecting RAGE protein levels or nuclear accumulation of HIF-1α. Treatment of hypoxic tumor cells with HMGB1 and BzATP ligands, respectively, of RAGE and P2X7R, activated a signaling pathway that, through Akt and Erk phosphorylation, determines nuclear accumulation of NF-κB and increases cell invasion. Inhibition of Akt by SH5 and Erk by INH1 prevented both nuclear translocation of NF-κB and cell invasion. Moreover, silencing RAGE and P2X7R abolished nuclear accumulation of NF-κB as well as cell invasion without affecting HIF-1α stabilization. Once in the nucleus, NF-κB would contribute to cell survival and invasion under hypoxia, by maintaining RAGE and P2X7R expression levels and matrix metalloproteinases 2 and 9 synthesis. These results show that, hypoxia can upregulate expression levels of membrane receptors that, by binding extracellular molecules eventually released by necrotic cells, contribute to the increased invasiveness of transformed tumor cells. Moreover, these observations strengthen our working hypothesis that upregulation of damage-associated molecular patterns receptors by HIF-1α represents the crucial event bridging hypoxia and inflammation in obtaining the malignant phenotype.

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells.

OBJECTIVE: As a better understanding of the molecular basis of carcinogenesis has emerged, oncogene-specific cell-signaling pathways have been successfully targeted to treat human malignances. Despite impressive advances in oncogene-directed therapeutics, genetic instability in cancer cells often manifest acquired resistance. This is particularly noted in the use of tyrosine kinase inhibitors therapies and not more evident than for chronic myeloid leukemia. Therefore, it is of great importance to understand the molecular mechanisms affecting cancer cell sensitivity and resistance to tyrosine kinase inhibitors. MATERIALS AND METHODS: In this study, we used continuous exposure to stepwise increasing concentrations of imatinib (0.6-1 µM) to select imatinib-resistant K562 cells. RESULTS: Expression of BCR-ABL increased both at RNA and protein levels in imatinib-resistant cell lines. Furthermore, expression levels of sphingosine kinase 1 (SphK1) were increased significantly in resistant cells, channeling sphingoid bases to the SphK1 pathway and activating sphingosine-1-phosphate-dependent tyrosine phosphorylation pathways that include the adaptor protein Crk. The partial inhibition of SphK1 activity by N,N-dimethylsphingosine or expression by small interfering RNA increased sensitivity to imatinib-induced apoptosis in resistant cells and returned BCR-ABL to baseline levels. To determine the resistance mechanism-induced SphK1 upregulation, we used pharmacological inhibitors of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway and observed robust downmodulation of SphK1 expression and activity when AKT2, but not AKT1 or AKT3, was suppressed. CONCLUSIONS: These results demonstrate that SphK1 is upregulated in imatinib-resistant K562 cells by a pathway contingent on a phosphoinositide 3-kinase/AKT2/mammalian target of rapamycin signaling pathway. We propose that SphK1 plays an important role in development of acquired resistance to imatinib in chronic myeloid leukemia cell lines.

Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients.

In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail.

2,3,7,8-Tetrachlorodibenzo-p-dioxin modifies expression and nuclear/cytosolic localization of bovine herpesvirus 1 immediate-early protein (bICP0) during infection.

Our previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases Bovine Herpesvirus 1 (BHV-1) replication through a dose-dependent increase in cytopathy and increased viral titer. Furthermore, TCDD was able to trigger BHV-1-induced apoptosis by up-regulating the activation of initiator caspases 8 and 9, as well as of effector caspase 3. Since TCDD activates caspase 3 after 4 h of infection, we have hypothesized an involvement of BHV-1 infected cell protein 0 (bICP0) in this process. Such protein, the major transcriptional regulatory protein of BHV-1, has been shown to indirectly induce caspase 3 activation and apoptosis. In order to elucidate the role of bICP0 in this apoptotic pathway, here we have analyzed the effects of TCDD on bICP0 expression. Following infection of bovine cells with BHV-1, we detected apoptotic features already at 12 h after infection, only in TCDD exposed groups. Furthermore, in the presence of different doses of TCDD, we observed a time-dependent modulation and increase of bICP0 gene expression levels, as revealed by RT-PCR analysis. Western blot analysis and immunocytochemistry revealed that TCDD induced an increase of bICP0 protein levels in a dose-dependent manner, compared to unexposed groups. Moreover, Western blot analysis of nuclear and cytosolic fractions of infected cells revealed that TCDD anticipated the presence of bICP0 protein in the cytoplasm. In conclusion, both the increase of replication of BHV-1 and anticipation of BHV-1-induced apoptosis could be the result of a relationship between TCDD and bICP0.

The effect of marathon on mRNA expression of anti-apoptotic and pro-apoptotic proteins and sirtuins family in male recreational long-distance runners.

BACKGROUND: A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circulating human lymphocytes leading to lipid peroxidation, DNA damage, mitochondrial perturbations, and protein oxidation.In our research, we investigated the effect of physical load on the extent of apoptosis in primary cells derived from blood samples of sixteen healthy amateur runners after marathon (a.m.). RESULTS: Blood samples were collected from ten healthy amateur runners peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and bcl-2, bax, heat shock protein (HSP)70, Cu-Zn superoxide dismutase (SOD), Mn-SOD, inducible nitric oxide synthase (i-NOS), SIRT1, SIRT3 and SIRT4 (Sirtuins) RNA levels were determined by Northern Blot analysis. Strenuous physical load significantly increased HSP70, HSP32, Mn-SOD, Cu-Zn SOD, iNOS, GADD45, bcl-2, forkhead box O (FOXO3A) and SIRT1 expression after the marathon, while decreasing bax, SIRT3 and SIRT4 expression (P < 0.0001). CONCLUSION: These data suggest that the physiological load imposed in amateur runners during marathon attenuates the extent of apoptosis and may interfere with sirtuin expression.

In vitro anti-leukaemia activity of pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs).

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of myeloid leukemia cells in the bone marrow and accumulation of these cells in the blood. CML represents approximately 15-20% of all adult leukemia and the disease development is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL. It is encoded by the Bcr-Abl fusion gene sequence as the result of chromosome 9/22 translocation (Philadelphia chromosome) or other aberrant cytogenetic events. The development of targeted agents that specifically inhibit the tyrosine kinase (TK) activity of BCR-ABL has revolutionized the treatment of CML. Imatinib is now the first-line treatment for chronic phase CML, and several newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have been added to the pharmacologic compendium. Despite the proven efficacy of TKIs to induce hematological and cytogenetic remission, the large majority of patients still have molecularly detectable disease. Therefore, new options are needed to improve therapeutic success in the treatment of leukemia. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from CML patients at onset or from patients in blast crisis and who were imatinib- dasatinib- and nilotinib resistant. These results suggests that these compounds are promising agent for the treatment of leukemia. Due to the fact that the phenomenon of resistance to TKIs remains a major issue in the treatment of patients with CML, the identification of new drugs may be of clinical relevance. This review summarises patents and papers dealing with the present understanding of mechanism of action and the most relevant data concerning TKs inhibition.