Acute myeloid leukemia AML is an aggressive group of cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS, rotenone, cytarabine, etoposide, ABT venetoclax , and carbonyl cyanide m -chlorophenylhydrazone] were each paired with six compounds with other activities, including tyrosine kinase inhibitors midostaurin and dasatinib , glycolytic inhibitors 2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine , and the microtubule destabilizer vinorelbine. Four combinations IACS with vinorelbine, rotenone with 2-deoxy-D-glucose, carbonyl cyanide m -chlorophenylhydrazone with dasatinib, and venetoclax with lonidamine showed synergistic cytotoxicity in both AML cell lines and were selective for tumor cells, as survival of healthy PBMCs was dramatically higher. Finally, two of the four combinations retained high synergy and strong selectivity in primary AML cells from patient samples, supporting the potential of these treatments for patients. Acute myeloid leukemia AML is a heterogeneous group of aggressive hematological malignancies that are characterized by the proliferation of undifferentiated or partially differentiated myelogenous blast cells. Despite efforts to improve treatment, front-line drug regimens for AML have remained essentially unchanged for 20 years, with the exception of very recent approvals of targeted therapies for a few patient populations e. Current front-line treatment for AML, called induction and consolidation, utilizes a combination of doxorubicin, daunorubicin, or idarubicin with cytarabine 1. In addition, relapse is a significant problem in AML, particularly due to a recurring population of leukemic cells that often remain resistant to frontline treatment or have acquired drug resistance 3.
Associated Data
Introduction
Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Previous reports demonstrate that metformin, an anti-diabetic drug, can decrease the risk of cancer and inhibit cancer cell growth. However, its mechanism in cancer cells is still unknown. Metformin significantly blocks cell cycle and inhibits cell proliferation and colony formation of leukemic cells. However, the apoptotic response to metformin varies. Furthermore, daily treatment with metformin induces apoptosis and reduces tumor growth in vivo. Metformin decreases electron transport chain complex I activity, oxygen consumption and mitochondrial ATP synthesis, while stimulating glycolysis for ATP and lactate production, pentose phosphate pathway for purine biosynthesis, fatty acid metabolism, as well as anaplerotic and mitochondrial gene expression.
ORIGINAL RESEARCH article
Bella G. Tumyan, Svetlana N. Zinzar, George J. Svet-Moldavsky, M. The histologic structure of these cysts was similar to that of corresponding sections of the gastrointestinal tract. Some of these cysts underwent spontaneous malignant conversion 13—16 months later: Adenocarcinomas of the small and large intestines, solid epithelial tumors, and sarcomas or leiomyosarcomas developed. Transplantable strains were obtained from these tumors. The growth of organ-like cysts, formed from fetal DT, was markedly retarded in the newborn recipients as compared with that in adults. Growth of transplantable tumors of DT was significantly retarded in newborn recipients as compared with that in adults.
Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development.