RESUMO
ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.
RESUMO
Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
RESUMO
Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfócitos Intraepiteliais/transplante , Leucemia/terapia , Animais , Antineoplásicos Imunológicos/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Leucemia/genética , Leucemia/imunologia , Leucemia/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Cell adhesion to stromal support and the associated intracellular signaling are central to drug resistance, therefore blocking both has been effective in increasing drug sensitization in leukemia. The stromal Ser/Thr protein kinase C (PKC) has been found to be important for conferring protection to leukemic cells. We aimed at elucidating the intracellular signals connected to cell adhesion and to stromal PKC. We found that NF-κB and Akt were up-regulated in mesenchymal stem cells (MSC) after binding of B-cell acute lymphoblastic leukemia (B-ALL) cells. Nevertheless, Akt inhibition did not induce B-ALL cell detachment. In spite of a clear activation of the NF-κB signaling pathway after B-ALL cell binding (up-regulation NF-κB1/2, and down-regulation of the IKBε and IKBα inhibitors) and an important reduction in cell adhesion after NF-κB inhibition, sensitization to the drug treatment was not observed. This was opposite to the PKC inhibitors Enzastaurin and HKPS, a novel chimeric peptide inhibitor, that were able to increase sensitization to dexamethasone, methotrexate, and vincristine. PLCγ1, Erk1/2, and CREB appear to be related to PKC signaling and PKC effect on drug sensitization since they were contra-regulated by HKPS when compared to dexamethasone-treated cells. Additionally, PKC inhibition by HKPS, but not by Enzastaurin, in MSC reduced the activity of three ABC transporters in leukemic cells treated with dexamethasone, a new indirect mechanism to increase sensitization to drug treatment in B-ALL cells. Our results show the validity of targeting the functional characteristic acquired and modulated during cell-to-cell interactions occurring in the leukemic niche.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Células Precursoras de Linfócitos B/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Adesão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , NF-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células Tumorais CultivadasRESUMO
Mesenchymal stem cells (MSC) favour a scenario where leukemic cells survive. The protein kinase C (PKC) is essential to confer MSC support to leukemic cells and may be responsible for the intrinsic leukemic cell growth. Here we have evaluated the capacity of a chimeric peptide (HKPS), directed against classical PKC isoforms, to inhibit leukemic cell growth. HKPS was able to strongly inhibit viability of different leukemic cell lines, while control HK and PS peptides had no effect. Further testing showed that 30% of primary samples from paediatric B-cell acute lymphoblastic leukaemia (B-ALL) were also strongly affected by HKPS. We showed that HKPS disrupted the supportive effect of MSC that promote leukemic cell survival. Interestingly, ICAM-1 and VLA-5 expression increased in MSC during the co-cultures with B-ALL cells, and we found that HKPS inhibited the interaction between MSC and B-ALL cells due to a reduction in the expression of these adhesion molecules. Of note, the susceptibility of B-ALL cells to dexamethasone increased when MSC were treated with HKPS. These results show the relevance of these molecular interactions in the leukemic niche. The use of HKPS may be a new strategy to disrupt intercellular communications, increasing susceptibility to therapy, and at the same time, directly affecting the growth of PKC-dependent leukemic cells.