The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells.
OBJECTIVE
The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a translocator protein (18KDa) (TSPO) ligand, facilitates the induction of cell death by a variety of cytotoxic and chemotherapeutic agents. Primary chronic lymphocytic leukemia (CLL) cells overexpress TSPO. The aim of this study was to examine the effects of PK11195 on CLL cells. Table 1. Characteristics of the patients with chronic lymphocytic leukemia.


METHODS
Using cytometric analysis, we studied the cytotoxic effects of PK11195 on peripheral B and T lymphocytes from patients with CLL and from healthy donors. Western blot and cytometric analyses were used to study the mitochondrial effects of PK11195 on CLL cells. Moreover, we analyzed the cytotoxic effect of PK11195 in patients' cells with mutated p53 or ATM.


RESULTS
PK11195 induces apoptosis and had additive effects with chemotherapeutic drugs in primary CLL cells. Other TSPO ligands such as RO 5-4864 and FGIN-1-27 also induce apoptosis in CLL cells. PK11195 induces mitochondrial depolarization and cytochrome c release upstream of caspase activation, and dithiocyana-tostilbene-2,2- disulfonic acid (DIDS), a voltage-dependent anion channel (VDAC) inhibitor, inhibits PK11195-induced apoptosis, demonstrating a direct involvement of mitochondria. CLL cells and normal B cells are more sensitive than T cells to PK11195-induced apoptosis. Interestingly, PK11195 induced apoptosis in CLL cells irrespective of their p53 or ATM status.


CONCLUSIONS
These results suggest that PK11195 alone or in combination with chemotherapeutic drugs might be a new therapeutic option for the treatment of CLL.
Santidrián
Antonio F
AF
Departament de Ciències Fisiològiques II, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Cosialls
Ana M
AM
Coll-Mulet
Llorenç
L
Iglesias-Serret
Daniel
D
de Frias
Mercè
M
González-Gironès
Diana M
DM
Campàs
Clara
C
Domingo
Alicia
A
Pons
Gabriel
G
Gil
Joan
J
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000378:metabolism; D001570:Benzodiazepinones / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D007210:Indoleacetic Acids; D007546:Isoquinolines; D018079:Receptors, GABA; C499229:TSPO protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050994:Voltage-Dependent Anion Channels; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C028513:4'-chlorodiazepam; D045304:Cytochromes c; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020169:Caspases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; C037850:PK 11195