RESUMO
Artificial intelligence (AI) platforms, such as Generative Pretrained Transformer (ChatGPT), have achieved a high degree of popularity within the scientific community due to their utility in providing evidence-based reviews of the literature. However, the accuracy and reliability of the information output and the ability to provide critical analysis of the literature, especially with respect to highly controversial issues, has generally not been evaluated. In this work, we arranged a question/answer session with ChatGPT regarding several unresolved questions in the field of cancer research relating to therapy-induced senescence (TIS), including the topics of senescence reversibility, its connection to tumor dormancy, and the pharmacology of the newly emerging drug class of senolytics. ChatGPT generally provided responses consistent with the available literature, although occasionally overlooking essential components of the current understanding of the role of TIS in cancer biology and treatment. Although ChatGPT, and similar AI platforms, have utility in providing an accurate evidence-based review of the literature, their outputs should still be considered carefully, especially with respect to unresolved issues in tumor biology. SIGNIFICANCE STATEMENT: Artificial Intelligence platforms have provided great utility for researchers to investigate biomedical literature in a prompt manner. However, several issues arise when it comes to certain unresolved biological questions, especially in the cancer field. This work provided a discussion with ChatGPT regarding some of the yet-to-be-fully-elucidated conundrums of the role of therapy-induced senescence in cancer treatment and highlights the strengths and weaknesses in utilizing such platforms for analyzing the scientific literature on this topic.
Assuntos
Inteligência Artificial , Neoplasias , Humanos , Reprodutibilidade dos Testes , SenoterapiaRESUMO
One of the most formidable challenges in oncology and tumor biology research is to provide an accurate understanding of tumor dormancy mechanisms. Dormancy refers to the ability of tumor cells to go undetected in the body for a prolonged period, followed by "spontaneous" escape. Various models of dormancy have been postulated, including angiogenic, immune-mediated, and cellular dormancy. While the former two propose mechanisms by which tumor growth may remain static at a population level, cellular dormancy refers to molecular processes that restrict proliferation at the cell level. Senescence is a form of growth arrest, during which cells undergo distinct phenotypic, epigenetic, and metabolic changes. Senescence is also associated with the development of a robust secretome, comprised of various chemokines and cytokines that interact with the surrounding microenvironment, including other tumor cells, stromal cells, endothelial cells, and immune cells. Both tumor and non-tumor cells can undergo senescence following various stressors, many of which are present during tumorigenesis and therapy. As such, senescent cells are present within forming tumors and in residual tumors post-treatment and therefore play a major role in tumor biology. However, the contributions of senescence to dormancy are largely understudied. Here, we provide an overview of multiple processes that have been well established as being involved in tumor dormancy, and we speculate on how senescence may contribute to these mechanisms.
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Células Endoteliais , Neoplasias , Humanos , Células Endoteliais/metabolismo , Neoplasias/patologia , Citocinas , Senescência Celular , Microambiente TumoralRESUMO
Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated ß-galactosidase, p21Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.
Assuntos
Doxorrubicina , Neoplasias , Humanos , Meios de Cultivo Condicionados , Doxorrubicina/farmacologia , Linhagem Celular , Fatores de Transcrição , Ativação do Complemento , Proteínas do Sistema ComplementoRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting adverse effect of anticancer therapy that complicates the lifestyle of many cancer survivors. There is currently no gold-standard for the assessment or management of CIPN. Subsequently, understanding the underlying mechanisms that lead to the development of CIPN is essential for finding better pharmacological therapy. Therapy-induced senescence (TIS) is a form of senescence that is triggered in malignant and non-malignant cells in response to the exposure to chemotherapy. Recent evidence has also suggested that TIS develops in the dorsal root ganglia of rodent models of CIPN. Interestingly, several components of the senescent phenotype are commensurate with the currently established primary processes implicated in the pathogenesis of CIPN including mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this article, we review the literature that supports the hypothesis that TIS could serve as a holistic mechanism leading to CIPN, and we propose the potential for investigating senotherapeutics as means to mitigate CIPN in cancer survivors.
Assuntos
Antineoplásicos , Sobreviventes de Câncer , Doenças do Sistema Nervoso Periférico , Humanos , Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/patologia , Estresse OxidativoRESUMO
Background and Objectives: The investigation of oncogenic viruses and their potential association with breast cancer (BC) remains an intriguing area of study. The current work aims to assess evidence of three specific viruses, human papillomavirus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in BC samples and to explore their relationship with relevant clinicopathological variables. Materials and Methods: The analysis involved BC samples from 110 Jordanian female patients diagnosed with BC and breast tissue samples from 30 control patients with no evidence of breast malignancy, investigated using real-time PCR. The findings were then correlated with various clinico-pathological characteristics of BC. Results: HPV was detected in 27 (24.5%), CMV in 15 (13.6%), and EBV in 18 (16.4%) BC patients. None of the control samples was positive for HPV or CMV while EBV was detected in only one (3.3%) sample. While (HPV/EBV), (HPV/CMV), and (EBV/CMV) co-infections were reported in 1.8%, 2.7%, and 5.5%, respectively, coinfection with the three viruses (HPV/CMV/EBV) was not reported in our cohort. A statistically significant association was observed between HPV status and age (p = 0.047), and between clinical stage and CMV infection (p = 0.015). Conclusions: Our findings indicate the presence or co-presence of HPV, CMV, and EBV in the BC subpopulation, suggesting a potential role in its development and/or progression. Further investigation is required to elucidate the underlying mechanisms that account for the exact role of oncoviruses in breast carcinogenesis.
Assuntos
Neoplasias da Mama , Citomegalovirus , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Feminino , Neoplasias da Mama/virologia , Jordânia/epidemiologia , Pessoa de Meia-Idade , Herpesvirus Humano 4/isolamento & purificação , Citomegalovirus/isolamento & purificação , Adulto , Idoso , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase em Tempo Real , Papillomavirus HumanoRESUMO
Background and Objectives: Human papillomavirus (HPV) was previously investigated in lung cancer with wide inter-geographic discrepancies. p16INK4a has been used as a surrogate for detecting high-risk HPV (HR-HPV) in some cancer types. This study assessed the evidence of HPV in non-small-cell lung cancer (NSCLC) among Jordanian patients, investigated the expression of p16INK4a, and evaluated its prognostic value and association with HPV status. Materials and Methods: The archived samples of 100 patients were used. HPV DNA detection was performed by real-time polymerase chain reaction (RT-PCR). p16INK4a expression was assessed by immunohistochemistry (IHC). The Eighth American Joint Committee on Cancer protocol (AJCC) of head and neck cancer criteria were applied to evaluate p16INK4a positivity considering a moderate/strong nuclear/cytoplasmic expression intensity with a distribution in ≥75% of cells as positive. Results: HPV DNA was detected in 5% of NSCLC cases. Three positive cases showed HR-HPV subtypes (16, 18, 52), and two cases showed the probable HR-HPV 26 subtype. p16INK4a expression was positive in 20 (20%) NSCLC cases. None of the HPV-positive tumors were positive for p16INK4a expression. A statistically significant association was identified between p16INK4a expression and the pathological stage (p = 0.029) but not with other variables. No survival impact of p16INK4a expression was detected in NSCLC cases as a group; however, it showed a statistically significant association with overall survival (OS) in squamous cell carcinoma (SqCC) cases (p = 0.033). Conclusions: This is the first study to assess HPV and p16INK4a expression in a Jordanian population. HPV positivity is rare in NSCLC among a Jordanian subpopulation. P16 INK4a reliability as a surrogate marker for HPV infection in lung cancer must be revisited.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidor p16 de Quinase Dependente de Ciclina , Neoplasias Pulmonares , Infecções por Papillomavirus , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , DNA Viral/análise , Papillomavirus Humano , Imuno-Histoquímica , Jordânia/epidemiologia , Neoplasias Pulmonares/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence-TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies.
Assuntos
Antineoplásicos , Neoplasias , Envelhecimento/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Senescência Celular/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , PoliploidiaRESUMO
The capability of tumour cells to escape from therapy-induced senescence, as well as cell-non-autonomous functions of senescence, support the premise that senescence could serve as one pathway to tumour dormancy (among others that include quiescence and diapause) that is permissive for disease recurrence. Consequently, the pharmacologic targeting of senescent tumour cells could mitigate the risk for cancer resurgence, thereby enhancing the therapeutic efficacy of cancer chemotherapy.
Assuntos
Senescência Celular , Neoplasias , Humanos , Neoplasias/patologiaRESUMO
Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence. Oncogenic processes that induce senescence include overexpression/hyperactivation of H-Ras, B-Raf, and cyclin E as well as inactivation of PTEN. Oncogenic viruses, such as Human Papilloma Virus (HPV), have also been shown to induce senescence. High-risk strains of HPV drive the immortalization, and hence transformation, of cervical epithelial cells via several mechanisms, but primarily via deregulation of the cell cycle, and possibly, by facilitating escape from senescence. Despite the wide and successful utilization of HPV vaccines in reducing the incidence of cervical cancer, this measure is not effective in preventing cancer development in individuals already positive for HPV. Accordingly, in this commentary, we focus on the potential contribution of oncogene and HPV-induced senescence (OIS) in cervical cancer. We further consider the potential utility of senolytic agents for the elimination of HPV-harboring senescent cells as a strategy for reducing HPV-driven transformation and the risk of cervical cancer development.
Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Senescência Celular/genética , Senoterapia , Neoplasias do Colo do Útero/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , OncogenesRESUMO
Background and Objectives: The development of radioresistance is a fundamental barrier to successful glioblastoma therapy. Autophagy is thought to play a role in facilitating the DNA repair of DNA damage foci in radiation-exposed tumor cells, thus, potentially contributing to their restoration of proliferative capacity and development of resistance in vitro. However, the effect of autophagy inhibitors on DNA damage repair is not fully clear and requires further investigation. Materials and Methods: In this work, we utilized M059K (DNA-PKcs proficient) and M059J (DNA-PKcs deficient) glioma cell lines to investigate the role of autophagy inhibitors in the DNA repair of radiation-induced DNA damage. Cell viability following radiation was determined by trypan blue exclusion in both cell lines. Cell death and autophagy assays were performed to evaluate radiation-induced cell stress responses. DNA damage was measured as based on the intensity of phosphorylated γ-H2AX, a DNA double-stranded breaks (DSBs) marker, in the presence or absence of autophagy inhibitors. Results: The cell viability assay showed that M059J cells were more sensitive to the same dose of radiation (4 Gy) than M059K cells. This observation was accompanied by an elevation in γ-H2AX formation in M059J but not in M059K cells. In addition, the DAPI/TUNEL and Senescence-associated ß-galactosidase (SA-ß-gal) staining assays did not reveal significant differences in apoptosis and/or senescence induction in response to radiation, respectively, in either cell line. However, acridine orange staining demonstrated clear promotion of acidic vesicular organelles (AVOs) in both cell lines in response to 4 Gy radiation. Moreover, DNA damage marker levels were found to be elevated 72 h post-radiation when autophagy was inhibited by the lysosomotropic agent bafilomycin A1 (BafA1) or the PI3K inhibitor 3-methyl adenine (3-MA) in M059K cells. Conclusions: The extent of the DNA damage response remained high in the DNA-PKcs deficient cells following exposure to radiation, indicating their inability to repair the newly formed DNA-DSBs. On the other hand, radioresistant M059K cells showed more DNA damage response only when autophagy inhibitors were used with radiation, suggesting that the combination of autophagy inhibitors with radiation may interfere with DNA repair efficiency.
Assuntos
Glioma , Fosfatidilinositol 3-Quinases , Autofagia , Linhagem Celular Tumoral , DNA , Reparo do DNA , Glioma/tratamento farmacológico , Glioma/genética , Glioma/radioterapia , Humanos , Tolerância a Radiação/fisiologiaRESUMO
Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-ß-galactosidase staining (SA-ß-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy.
RESUMO
Senescence is a cell state that contributes to several homeostatic and pathologic processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction [oncogene-induced senescence (OIS)]. Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung. Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. Although senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This Emerging Concepts commentary will 1) summarize evidence in established models of OIS including B-Raf-induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models, as well as evidence from clinical precancerous lesions; 2) suggest that OIS is targetable; and 3) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions. SIGNIFICANCE STATEMENT: The treatment of premalignant lesions is largely based on the utilization of invasive (or minimally invasive) measures. Oncogene-induced senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. Although the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation. Accordingly, the pharmacological targeting of oncogene-induced senescent cells could potentially provide a novel, less invasive, means for the treatment of premalignant disease.
Assuntos
Lesões Pré-Cancerosas/tratamento farmacológico , Senoterapia/uso terapêutico , Animais , Senescência Celular/efeitos dos fármacos , Humanos , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/prevenção & controle , Senoterapia/farmacologiaRESUMO
BACKGROUND: Health Care Workers (HCWs), including medical doctors, played a pivotal role as a first-line defence against the COVID-19 pandemic. Because of high exposure, HCWs are at an increased risk of contracting the disease. AIMS: This study aims to assess the level of precautionary measures, both at home and the workplace, amongst medical doctors who were on duty during the national lockdown in Jordan. METHODS: A cross-sectional study was conducted between March 23 and May 1, 2020, utilising a self-administered web-based questionnaire to examine a sample of medical doctors (n = 270) working at different healthcare institutions in Jordan. Likert scale was used to code the data and generate means and percentages. RESULTS: The most practiced on-duty precautionary measures were cleaning hands with water and disinfectant for more than 20 seconds (47.4%), followed by proper hygiene before and during meals (38.9%). The most practiced off-duty measures were taking off clothes before entering the residential place (65.9%) and prohibiting visitors (58.1%). Overall, the mean work protection percentage score was 73.8% (range: 28%-100%), while the mean home safety percentage score was 71.3% (range: 25%-100%). Work protection score was positively correlated with the home safety score. Female doctors were found to be more precautious at home than males. Doctors with chronic illness(es) were found to be less precautious than their healthier counterparts. Participants who isolated themselves expressed the highest level of home safety practice. Doctors who reported to smoke were found more precautious at home and doctors who preferred to work during lockdowns were more precautious at the workplace. CONCLUSION: The level of precautionary behaviour of medical doctors in Jordan was not optimal. More attention and efforts are needed to enhance the adherence of doctors to precautionary guidance. Strengthening the role of infectious disease and infection control units within healthcare settings remains a necessity.
Assuntos
COVID-19 , Pandemias , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Jordânia , Masculino , SARS-CoV-2 , Inquéritos e QuestionáriosRESUMO
Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.
Assuntos
Autofagia , Senescência Celular , Quimiorradioterapia , Neoplasias , Células HCT116 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Autophagy, a conserved cellular process by which cells recycle their contents either to maintain basal homeostasis or in response to external stimuli, has for the past two decades become one of the most studied physiological processes in cell biology. The 2016 Nobel Prize in Medicine and Biology awarded to Dr. Ohsumi Yoshinori, one of the first scientists to characterize this cellular mechanism, attests to its importance. The induction and consequent completion of the process of autophagy results in wide ranging changes to the cellular proteome as well as the secretome. MS-based proteomics affords the ability to measure, in an unbiased manner, the ubiquitous changes that occur when autophagy is initiated and progresses in the cell. The continuous improvements and advances in mass spectrometers, especially relating to ionization sources and detectors, coupled with advances in proteomics experimental design, has made it possible to study autophagy, among other process, in great detail. Innovative labeling strategies and protein separation techniques as well as complementary methods including immuno-capture/blotting/staining have been used in proteomics studies to provide more specific protein identification. In this review, we will discuss recent advances in proteomics studies focused on autophagy.
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Autofagossomos/química , Autofagia/fisiologia , Proteoma/análise , Proteômica/métodos , Animais , Biomarcadores , Células/metabolismo , Homeostase/fisiologia , Humanos , Lisossomos/química , Espectrometria de Massas/tendências , Prêmio Nobel , Peptídeos/análise , Peptídeos/metabolismoRESUMO
BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. In addition to surgical resection, which is considered first-line treatment at early stages of the disease, chemotherapy and radiation are widely used when the disease is advanced. Of multiple responses that may occur in the tumor cells in response to cancer therapy, the functional importance of autophagy remains equivocal; this is likely to restrict current efforts to sensitize this malignancy to chemotherapy and/or radiation by pharmacological interference with the autophagic response. SCOPE OF REVIEW: In this review, we attempt to summarize the current state of knowledge based on studies that evaluated the function of autophagy in non-small cell lung cancer (NSCLC) cells in response to radiation and the most commonly used chemotherapeutic agents. MAJOR CONCLUSIONS: In addition to the expected prosurvival function of autophagy, where autophagy inhibition enhances the response to therapy, autophagy appears also to have a "non-cytoprotective" function, where autophagy blockade does not affect cell viability, clonogenicity or tumor volume in response to therapy. In other cases, autophagy may actually mediate drug action via expression of its cytotoxic function. GENERAL SIGNIFICANCE: These observations emphasize the complexity of autophagy function when examined in different tumor cell lines and in response to different chemotherapeutic agents. A more in-depth understanding of the conditions that promote the unique functions of autophagy is required in order to translate preclinical findings of autophagy inhibition to the clinic for the purpose of improving patient response to chemotherapy and radiation.
Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Medicina de Precisão , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Autofagia/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , HumanosRESUMO
Several breakthrough articles have recently confirmed the ability of tumor cells to escape the stable cell cycle arrest imposed by Therapy-Induced Senescence (TIS). Subsequently, accepting the hypothesis that TIS is escapable should encourage serious reassessments of the fundamental roles of senescence in cancer treatment. The potential for escape from TIS undermines the well-established tumor suppressor function of senescence, proposes it as a mechanism of tumor dormancy leading to disease recurrence and invites for further investigation of its unfavorable contribution to cancer therapy outcomes. Moreover, escaping TIS strongly indicates that the elimination of senescent tumor cells, primarily through pharmacological means, is a suitable approach for increasing the efficacy of cancer treatment, one that still requires further exploration. This commentary provides an overview of the recent evidence that unequivocally demonstrated the ability of therapy-induced senescent tumor cells in overcoming the terminal growth arrest fate and provides future perspectives on the roles of TIS in tumor biology.
Assuntos
Senescência Celular , Neoplasias , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
PURPOSE: In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E (Vit. E). METHODS: Adult male rats were injected with four doses of 2 mg/kg/week DOX, or 2 mg/kg PAC every other day intraperitoneally. Vit. E was co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. RESULTS: There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances (TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus, which was overcome by the co-administration of Vit. E. CONCLUSION: There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration.
Assuntos
Paclitaxel , Vitamina E , Ratos , Masculino , Animais , Vitamina E/farmacologia , Vitamina E/uso terapêutico , Paclitaxel/toxicidade , Ratos Wistar , Antioxidantes , Estresse Oxidativo , Doxorrubicina/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controleRESUMO
Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-ß-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.
Assuntos
Antineoplásicos , Neoplasias , Ratos , Animais , Cálcio , Cisplatino/toxicidade , Nociceptividade , Ratos Sprague-Dawley , Hiperalgesia , Antineoplásicos/toxicidadeRESUMO
Background: Implementing allergy testing among children with a reported history of penicillin allergy could be challenging, particularly in developing countries with limited resources. This study screened and risk-stratified the likelihood of true penicillin allergy among children labeled with penicillin allergy in Jordan. Methods: A web-based survey, completed by parents, assessed history, type, and severity of penicillin allergic reactions, including age at diagnosis, symptoms, time to the reaction, reaction's course and resolution, and received medical evaluation/testing. Low-risk allergic symptoms were defined as vomiting, diarrhea, headache, dizziness, itching, rash, cough, or runny nose without evidence of anaphylaxis or severe cutaneous reactions. Results: A total of 530 parents of "penicillin allergy"-labeled children completed the survey. Of these, 86.4% reported allergic reactions to penicillin and 13.6% reported avoidance of penicillin due to family history. Among the former, 52.2% were male, 67.3% were three years old or younger when the reported reaction was established, and 68.3% experienced exclusively low-risk symptoms. Overall, skin rash was the most reported symptom (86.0%). High-risk symptoms were reported in 31.5% of children. About two-thirds (64.0%) of children were reported to have experienced symptoms after the first exposure to penicillin. The most common indication for antibiotic use was a throat infection (63.8%). Asthma comorbidity was significantly higher among high-risk (24.8%) compared low-risk group (11.5%). Conclusion: In Jordan, many parent-reported penicillin allergic reactions seem to be clinically insignificant and unlikely to be verifiable, which can adversely affect patients' care and antimicrobial stewardship. An appropriate clinical history/evaluation is a key step in identifying true immunoglobulin E-mediated allergic reactions and risk stratifying patients for either de-labeling those with obviously non-immune-mediated reactions or identifying candidates for direct oral challenge test.