Dysregulation Of Apoptotic Pathways Research Articles

Small Cell Lung Cancer-An Update on Chemotherapy Resistance.

Compared to other types of lung cancer, small cell lung cancer (SCLC) exhibits aggressive characteristics that promote drug resistance. Despite platinum-etoposide chemotherapy combined with immunotherapy being the current standard treatment, the rapid development of drug resistance has led to unsatisfactory clinical outcomes. This review focuses on the mechanisms contributing to the chemotherapy resistance phenotype in SCLC, such as increased intra-tumoral heterogeneity, alterations in the tumor microenvironment, changes in cellular metabolism, and dysregulation of apoptotic pathways. A comprehensive understanding of these drug resistance mechanisms in SCLC is imperative for ushering in a new era in cancer research, which will promise revolutionary advancements in cancer diagnosis and treatment methodologies.

Necroptosis could serve as an indicator of therapeutic resistance in viral induced well-differentiated oral squamous cell carcinoma?

Goal of the perspectiveExploring necroptosis as an indicator of therapeutic resistance in viral-induced well-differentiated oral squamous cell carcinoma (OSCC) is to elucidate its potential role in predicting treatment outcomes and guiding therapeutic decisions. By understanding the relationship between necroptosis levels and therapeutic resistance, oncologists can aim to identify novel biomarkers and therapeutic targets that could improve patient management and outcomes in viral-induced OSCC. DiscussionViral-induced oral squamous cell carcinoma (OSCC) presents with disrupted cellular functions, dysregulation of apoptotic pathways, evasion of programmed cell death and resistance to conventional anticancer treatments. Concurrently, alterations in pro-inflammatory cytokines and chemokines drive tumorigenesis in viral-induced squamous cell carcinoma, impairing anti-viral immune responses. ConclusionMonitoring necroptosis levels in viral-induced OSCC offers insights into therapy resistance, as high levels may indicate reduced responsiveness to standard treatments. Understanding the role of necroptosis in therapy resistance could pave the way for the development of targeted therapies that exploit necroptosis pathways to overcome resistance and improve treatment outcomes in viral-induced OSCC.

Activation of Simultaneous Apoptosis and Necroptosis to Eradicate Drug Resistant Leukemia

Dysregulation of apoptotic pathways provides an indiscriminate mechanism for refractory acute lymphoblastic leukemia (ALL) to escape cell death induced by many chemotherapeutic compounds. Here we have assessed the potential of SMAC mimetic (SM) compounds to short circuit cell death resistance by blocking the pro-survival cellular inhibitor of apoptosis (cIAP) proteins. By screening a large set of patient-derived precursor B-cell ALL samples in an ex vivo model of the leukemia microenvironment we detect exquisite sensitivity to two different SM compounds, Birinapant and LCL161, in about one third of ALL samples. Strong ex vivo SM activity correlated with potent in vivo anti-leukemic efficacy against de novo refractory and relapsed ALL xenografts. Intriguingly, we find that although SM-sensitivity is independent of TNF and TNFR1 levels, expression of TNFR2 is highly predictive of response to SM in two separate cohorts of ALL samples, suggesting that TNFR2 expression may represent a promising biomarker for identifying SM-sensitive cells. Downstream, we employ a novel and powerful multi-colour Lenti-CRISPR approach to show that simultaneous disruption of both apoptotic and necroptotic genes is necessary to block SM-induced death. In contrast, disruption of RIP1 alone was adequate to block SM-induced apoptosis and necroptosis. Surprisingly, RIP1 loss had no significant impact on response to standard anti-leukemic therapies, supporting a view that the RIP1-dependent death pathway is not likely to be selected against in leukemia cells that have failed to respond to front line therapy. These results provide the first evidence that SM compounds can circumvent apoptotic escape in drug-refractory ALL through parallel activation of both RIP1-dependent apoptosis and necroptosis. Furthermore, our data strongly support further development of SM as anti-leukemic agents for treatment in resistant disease. DisclosuresNo relevant conflicts of interest to declare.

Apoptosis-reactivating agents for targeted anticancer therapy

The review considers the current knowledge on molecular mechanisms of apoptosis. Particular emphasis is given to the key elements of the extrinsic death receptor pathway and the intrinsic mitochondrial pathway. Dysregulation of apoptotic pathways is considered as a key factor in the survival of cancer cells in response to conventional chemotherapeutic drugs or radiation therapy. Substances that selectively reactivate apoptosis in malignant cells are considered as the promising candidate anticancer drugs, which have now entered various phases of clinical trials. The modern techniques allowing non-invasive visualization of apoptotic cells with special reference to therapy-induced cell death are briefly surveyed.

Inhibition of Apoptosis in Pediatric Cancer by Survivin

An estimated 17.6 per 100,000 new cases of childhood cancer are diagnosed each year in the United States. The major subtypes of childhood cancer include leukemia, central nervous system tumors, lymphoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, Germ cell tumors, and other rare tumors. Despite improvements in the diagnosis and treatment of these tumors over the last 30 years, subsets of children still have poor outcomes and many others have significant morbidity. Dysregulation of apoptotic pathways has been shown to contribute to tumor formation as well as resistance to therapy in both pediatric and adult malignancies. Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is highly expressed in diverse cancers and correlates with decreased patient survival. Here, we review the current literature on Survivin expression in pediatric cancer, its relationship to clinical outcome and potential therapeutic options to target this protein in pediatric cancer.

The Role of Apoptosis in Cancer Development and Treatment: Focusing on the Development and Treatment of Hematologic Malignancies

Apoptosis is a normal aspect of human physiology ensuring tissue homeostasis. Evasion of endogenous cell death processes, including apoptosis, represents one of the characteristics of cancer. Defects in the physiological mechanisms of apoptosis contribute to the pathological cell expansion and to the development and progression of cancer. Resistance of malignant cells to cancer therapeutic agents may be, in some cases, caused by dysregulation of apoptotic pathways, e.g. BCL2 or IAP overexpression. The understanding of the physiological mechanisms that control apoptosis and the elucidation of apoptotic defects in cancer cells may lead to the development of targeted cancer therapies. Apoptotic pathways, molecules involved in the cross-talk between individual apoptosis pathways and promising new anti-cancer agents, which trigger directly or indirectly apoptosis of hematologic cancer cells, are reviewed in this article.

Clinical impact of crosstalk during apoptosis induction

Dysregulation of apoptotic pathways is an important factor in cancer development. Increasing knowledge of the various factors and mechanisms involved has provided the basis for development of novel anti-cancer strategies. However, therapeutic approaches based on these strategies might be hampered by the occurrence of resistant populations. The knowledge of the underlying mechanism will provide the intellectual basis to overcome these possible limitations.

Detection of BCL2 Rearrangements in Follicular Lymphoma

The identification and characterization of recurrent chromosomal translocations has improved tumor classification and yielded numerous insights into tumor pathogenesis, as such events typically lead to the dysregulation of proteins that control critical cellular processes, such as apoptosis, proliferation, differentiation, and immortalization. A prototypical example of such a chromosomal translocation is the (14;18)(q32;q32), which is highly associated with the B cell neoplasm follicular lymphoma. 1 Molecular analyses of DNA isolated from follicular lymphoma cells in the mid-1980’s showed that the t(14;18) creates a derivative chromosome 14 on which the BCL2 gene is juxtaposed to immunoglobulin heavy chain gene (IgH) sequences, 2-5 including enhancer sequences that override normal BCL2 gene control elements and drive inappropriately high levels of BCL2 expression in follicle center B cells. 6,7 Subsequently, several groups noted that enforced expression of BCL2 transgenes in murine hematopoietic cells promoted cell survival, 8,9 the first indication of the anti-apoptotic activity of BCL2. BCL2 transgenic mice also showed increased susceptibility to autoimmune disease 10 and B cell lymphoma, 11 observations that helped to foster the now generally accepted idea that dysregulation of apoptotic pathways is important in the pathogenesis of many forms of cancer and autoimmune disorders. These effects of BCL2 appear to be mediated through sequestration of “BH3 domain only” pro-apoptotic proteins such as BAD, BIM, and NOXA, 12 which resets the apoptotic “rheostat” toward increased resistance to programmed cell death. In addition to its impact on our thinking about cancer pathophysiology, the molecular characterization of the t(14;18) and its downstream consequences has influenced our approach to the diagnosis of hematological malignancy in several ways. The t(14;18) was an early example of an acquired genetic lesion that was strongly associated with a particular neoplasm, and thus of utility in tumor classification. Juxtaposed BCL2 and IgH DNA sequences provide a tumor-specific marker that can be exploited in the detection of minimal residual disease. 13,14 Furthermore, because BCL2 is down-regulated in normal germinal center B cells, 15 its expression (or lack thereof) can help to distinguish reactive and neoplastic follicles. 16 Finally, the presence of the t(14;18) has been suggested to be a marker of poor prognosis in diffuse large B cell lymphoma 17,18 (possibly because some such tumors arise through transformation of unrecognized underlying follicular lymphomas), although it must be said that more recent studies have not detected such a correlation. 19-21 These relationships have prompted the development of multiple methods that aim to detect the t(14;18) in tissue specimens. In this issue of The American Journal of Pathology, Albinger-Hegyi et al 22 report a new set of polymerase chain reaction (PCR)-based tests for detection of the BCL2/IgH fusion genes that offer some significant advantages in sensitivity over other more commonly used PCR-based methods. This commentary will attempt to place this contribution in context by discussing the advantages and limitations of various tests that aim to detect the t(14;18) or its downstream consequences.

Apoptosis and the immune system.

Apoptosis is a physiological process of cell death that occurs as part of normal development and in response to a variety of physiological and pathophysiological stimuli. The effector mechanisms which carry out the death program are well preserved across species and evolution. Apoptosis is important in the immune system, and plays significant roles in the control of the immune response, the deletion of immune cells recognising self-antigens, and cytotoxic killing. Some of the molecular regulators of these processes, such as CD95 and bcl-2 family proteins are the subjects of intense research. Malfunctioning of the immune system may lead to increased or decreased cell death. Conversely, dysregulation of apoptotic pathways themselves may lead to a spectrum of human disease, including autoimmune disease and immunodeficiency.