F16, a mitochondriotoxic compound, triggers apoptosis or necrosis depending on the genetic background of the target carcinoma cell.
Mutations that lead to the emergence of resistance to apoptosis are commonly observed among tumor cells. Some of the proteins affected are integral parts of the apoptotic cascade such as pro- and antiapoptotic members of the Bcl-2 family. F16 is a small molecule that accumulates in mitochondria of a variety of tumor cells and interferes with their physiological function. Because this interference ultimately triggers apoptosis in many affected cell lines, we examined the effect of antiapoptotic Bcl-2 overexpression on the response of cells to F16. Our results showed that high levels of Bcl-2 did not block the ability of F16 to induce cell death. However, unlike the apoptotic response that followed F16 treatment of cells with moderate Bcl-2 levels, cells resistant to a variety of apoptotic stimuli by virtue of Bcl-2 overexpression succumbed to F16 by necrosis. Thus, this dual ability of the mitochondriotoxic compound F16 to induce apoptosis and necrosis may represent an added advantage by expanding its spectrum of action toward genetically altered tumor cells incapable of apoptosis.
Fantin
Valeria R
VR
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Leder
Philip
P
D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006706:Homeostasis; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D010084:Oxidation-Reduction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011726:Pyridinium Compounds / Q000633:toxicity*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011726:Pyridinium Compounds; C471842:4-(2-(indol-3-yl)vinyl)-1-methylpyridinium