nitrophenols and Hematologic-Neoplasms

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; United States; United States Food and Drug Administration

Blocks in apoptosis are now widely regarded as key pathophysiological maladaptations critical for tumour persistence. Importantly, it has also been recognised that they confer resistance to cytotoxic therapy, and hence often portend an adverse prognosis. The advent of BH3-mimetics represents a nascent clinical capability to directly reverse the evasion of apoptosis, and indeed exploit the very molecular abnormalities which have hitherto posed major obstacles to therapeutic success. Clinical trials with BH3-mimetics have demonstrated clear single agent anti-tumour activity in selected haematological malignancies. These drugs also offer promise as adjuncts to existing or emerging therapies in a broader range of cancers.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Hematologic Neoplasms; Humans; Indoles; Molecular Mimicry; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

Programmed cell death of non-nucleated blood cells - platelets - could be associated with pathophysiology of oncologic and oncohematologic diseases. It contributes to both bleedings (caused by the thrombocytopenia, which is induced by elimination of the platelets) and thrombosis (caused by the processes of blood coagulation on the surface of phosphatidylserine exposing platelets). Here we characterized functional responses of platelets from the patients with various oncological disorders undergoing chemotherapy and compared them to the platelets from the healthy donors and platelets pre-incubated with apoptosis inducer ABT-737. Some patients exhibited diminished capability of platelets to aggregate. Immunophenotyping of these platelets revealed their pre-activation in comparison to the platelets from the healthy donors. Calcium signaling analysis revealed that in the patient-derived platelets, as well as in the apoptotic platelets, intracellular calcium levels were increased in resting cells. However, moderate level of this increase together with weak expression of phosphatidylserine allows us to assume that apoptotic processes in the circulating platelets from the patients are limited.

Topics: Adolescent; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Blood Coagulation; Blood Platelets; Calcium; Child; Child, Preschool; Female; Hematologic Neoplasms; Humans; Male; Nitrophenols; Phosphatidylserines; Piperazines; Sulfonamides