Indole-3-Carbinol Synergizes with and Restores Fludarabine Sensitivity in Chronic Lymphocytic Leukemia Cells Irrespective of p53 Activity and Treatment Resistances.
OBJECTIVE
Chronic lymphocytic leukemia (CLL) still is lacking a cure. Relapse and development of refractoriness to current treatments are common. New therapies are needed to improve patient prognosis and survival.


METHODS
Indole-3-carbinol (I3C) is a natural product with antitumor properties already clinically tested. The effect of I3C, F-ara-A, and combinations of both drugs on CLL cells from patients representing different Rai stages, IGHV mutation status, cytogenetic alterations, p53 functionality, and treatment resistances was tested, as well as the toxicity of these treatments in mice.


RESULTS
I3C induces cytotoxicity in CLL cells but not in normal lymphocytes. I3C strongly synergized with F-ara-A in all CLL cells tested, including those with p53 deficiency and/or F-ara-A resistance. The mechanism of cell death involved p53-dependent and -independent apoptosis. The combination of I3C + F-ara-A was equally effective in CLL cells irrespective of IGHV mutation stage and patient refractoriness. Moreover, CLL survival and treatment resistance induced by co-culturing CLL cells on stroma cells were overcome by the combinatory I3C + F-ara-A treatment. No toxicity was associated with the combined I3C + fludarabine treatment in mice.


CONCLUSIONS
I3C in combination with F-ara-A is highly cytotoxic in CLL cells from refractory patients and those with p53 deficiency. The striking dose reduction index for F-ara-A in combination with I3C would reduce fludarabine toxicity while having a similar or better anti-CLL effectiveness. Moreover, the low toxicity of I3C, already clinically tested, supports its use as adjuvant and combinatory therapy in CLL, particularly for patients with relapsed or refractory disease.
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain. Instituto de Investigacion Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
Gema
G
Perez-Chacon
Servicio de Hematologia, Hospital General Universitario Gregorio Marañon, Madrid, Spain. Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
Carolina
C
Martinez-Laperche
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain.
Nerea
N
Rebolleda
Servicio de Inmunologia, Instituto de Investigacion Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
Beatriz
B
Somovilla-Crespo
Servicio de Inmunologia, Instituto de Investigacion Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
Cecilia
C
Muñoz-Calleja
Servicio de Hematologia, Hospital General Universitario Gregorio Marañon, Madrid, Spain. Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
Ismael
I
Buño
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain. Instituto de Investigacion Hospital Universitario La Paz (IDIPAZ), Madrid, Spain. jmzapata@iib.uam.es.
Juan M
JM
Zapata
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007211:Indoles / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D007211:Indoles; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C016517:indole-3-carbinol; D053453:Caspase 9; D014740:Vidarabine; C024352:fludarabine