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

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental design:</b> 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, <i>IGHV</i> mutation status, cytogenetic alterations, p53 functionality, and treatment resistances was tested, as well as the toxicity of these treatments in mice.</p><p><b>Results:</b> 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 <i>IGHV</i> 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(1); 134–45. ©2015 AACR</i>.</p></div>