ABSTRACT
Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.
Subject(s)
Antineoplastic Agents/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Neoplasms/metabolism , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Proliferation , Citric Acid Cycle/drug effects , Electron Transport/drug effects , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Mitochondria/genetics , Mitochondrial Dynamics/drug effects , Protein Biosynthesis/drug effectsABSTRACT
Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. ©2018 AACR.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Biopsy , Bone Marrow/pathology , Caprylates/administration & dosage , Cell Line , Cell Respiration/drug effects , Cytarabine/administration & dosage , Drug Resistance, Neoplasm , Female , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Mice , Middle Aged , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Mitoxantrone/administration & dosage , Neoplasm Grading , Neoplasm Staging , Oxygen Consumption/drug effects , Recurrence , Retreatment , Sulfides/administration & dosage , Treatment Outcome , Young AdultABSTRACT
Regulation of nuclear transport is an essential component of apoptosis. As chemotherapy induced cell death progresses, nuclear transport and the nuclear pore complex (NPC) are slowly disrupted and dismantled. 5-Fluorouracil (5-FU) and the camptothecin derivatives irinotecan and topotecan, are linked to altered nuclear transport of specific proteins; however, their general effects on the NPC and transport during apoptosis have not been characterized. We demonstrate that 5-FU, but not topotecan, increases NPC permeability, and disrupts Ran-mediated nuclear transport before the disruption of the NPC. This increased permeability is dependent on increased cellular calcium, as the Ca2+ chelator BAPTA-AM, abolishes the effect. Furthermore, increased calcium alone was sufficient to disrupt the Ran gradient. Combination treatments of 5-FU with topotecan or irinotecan, similarly disrupted nuclear transport before disassembly of the NPC. In both single and combination treatments nuclear transport was disrupted before caspase 9 activation, indicating that 5-FU induces an early caspase-independent increase in NPC permeability and alteration of nuclear transport. Because Crm1-mediated nuclear export of tumor suppressors is linked to drug resistance we also examined the effect of 5-FU on the nuclear export of a specific target, topoisomerase. 5-FU treatment led to accumulation of topoisomerase in the nucleus and recovered the loss nuclear topoisomerase induced by irinotecan or topotecan, a known cause of drug resistance. Furthermore, 5-FU retains its ability to cause nuclear accumulation of p53 in the presence of irinotecan or topotecan. Our results reveal a new mechanism of action for these therapeutics during apoptosis, opening the door to other potential combination chemotherapies that employ 5-FU as a calcium mediated inhibitor of Crm1-induced nuclear export of tumor suppressors.
