Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore

Abstract

The molecular mode of action of lonidamine, a therapeutic agent employed in cancer chemotherapy, has been elusive. Here we provide evidence that lonidamine (LND) acts on mitochondria to induce apoptosis. LND provokes a disruption of the mitochondrial transmembrane potential which precedes signs of nuclear apoptosis and cytolysis. The mitochondrial and cytocidal eects of LND are not prevented by inhibitors of caspases or of mRNA or protein synthesis. However, they are prevented by transfection-enforced overexpression of Bcl-2, an oncoprotein which inhibits apoptosis by stabilizing the mitochondrial membrane barrier function. Accordingly, the cell death-inducing eect of LND is ampli®ed by simultaneous addition of PK11195, an isoquinoline ligand of the peripheral benzodiazepine receptor which antagonizes the cytoprotective eect of Bcl-2. When added to isolated nuclei, LND fails to provoke DNA degradation unless mitochondria are added simultaneously. In isolated mitochondria, LND causes the dissipation of the mitochondrial inner transmembrane potential and the release of apoptogenic factors capable of inducing nuclear apoptosis in vitro. Thus the mitochondrion is the subcellular target of LND. All eects of LND on isolated mitochondria are counteracted by cyclosporin A, an inhibitor of the mitochondrial PT pore. We therefore tested the eect of LND on the puri®ed PT pore reconstituted into liposomes. LND permeabilizes liposomal membranes containing the PT pore. This eect is prevented by addition of recombinant Bcl-2 protein but not by a mutant Bcl-2 protein that has lost its apoptosisinhibitory function. Altogether these data indicate that LND represents a novel type of anti-cancer agent which induces apoptosis via a direct eect on the mitochondrial PT pore.

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

“…The main side effects of this drug include prolongation of the cardiac QT interval, torsade de pointes, congestive heart failure, hypokalemia, hypomagnesemia, and leukocytosis (16). Lonidamine, a derivative of indazole-3-carboxylic acid, also induces apoptosis through IMM potential (17). The most frequent toxicities of this drug are gastrointestinal and hematologic side effects (18).…”

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…In addition, many MDR cells over-express epidermal growth factor receptor (EGFR) (Franovic et al, 2007). Milane et al utilized this expression through development of EGFRtargeted, polymer blend nano-carriers to combat MDR cancer using paclitaxel (PTX) (Milane et al, 2011) and lonidamine (LON) (Del Bufalo et al, 1996;Ravagnan et al, 1999;Li et al, 2002),where a novel orthotopic model of MDR human breast cancer in nude mice was developed to evaluate the safety and efficacy of nano-particle (NP) treatment. They observed that treatment with the EGFRtargeted LON/PTX nano-particles decreased tumor density and altered the MDR phenotype of the tumor xenografts, which means that combination of LON/PTX therapy using EGFR-targeted NPs could be used as a new approach for the treatment of MDR cancer.…”

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

“…55 PBR, an OM protein, is a pharmacological target for cytotoxic drugs. Thus PBR ligands such as PK111195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-isoquinolinecarboxamide), FGIN-I-27 (N,B-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide), and chlorodiazepam enhance the apoptogenic effects of a variety of agents including TNF, 56 ceramide, doxorubicin, etoposide, 57 arsenite, 58 or lonidamine 59 and overcome the cytoprotective effects of Bcl-2. 57 ± 59…”