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Clin Cancer Res. 2016 Jan 1;22(1):134-45. doi: 10.1158/1078-0432.CCR-15-0736. Epub 2015 Aug 31.

Indole-3-Carbinol Synergizes with and Restores Fludarabine Sensitivity in Chronic Lymphocytic Leukemia Cells Irrespective of p53 Activity and Treatment Resistances.

Author information

1
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain. Instituto de Investigacion Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.
2
Servicio de Hematologia, Hospital General Universitario Gregorio Marañon, Madrid, Spain. Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), Madrid, Spain.
3
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain.
4
Servicio de Inmunologia, Instituto de Investigacion Sanitaria Hospital Universitario de La Princesa, Madrid, Spain.
5
Instituto de Investigaciones Biomedicas "Alberto Sols," CSIC/UAM, Madrid, Spain. Instituto de Investigacion Hospital Universitario La Paz (IDIPAZ), Madrid, Spain. jmzapata@iib.uam.es.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26324744
DOI:
10.1158/1078-0432.CCR-15-0736
[Indexed for MEDLINE]
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