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Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

Authors' Affiliations: ¹ Toronto General Research Institute-University Health Network; ² Sunnybrook Odette Cancer Centre; and ³ Medicine, ⁴ Medical Biophysics, and ⁵ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Eldad Zacksenhaus, Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, 67 College Street, Room 407, Toronto, Ontario, Canada M5G 2M1. Phone: 416-340-4800, ext. 5106; Fax: 416-340-3453; E-mail: eldad.zacksenhaus{at}utoronto.ca. Andrea Eisen, Preventive Oncology, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Phone: 416-480-4617; E-mail: andrea.eisen{at}sunnybrook.ca

Purpose: N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs).

Experimental Design: Human breast TICs from pleural effusions were identified as CD44⁺:CD24^–/low cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice.

Results: We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44⁺:CD24^–/low breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44⁺:CD24^–/low and CD44^–:CD24⁺ cells equally well, DPPE induced apoptosis preferentially in CD44⁺:CD24^–/low cells. Treatment of Her2/Neu⁺ mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells.

Conclusions: Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.