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Research Articles: Therapeutics

Cyclohexylpiperazine derivative PB28, a ₂ agonist and ₁ antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer

¹ Clinical Experimental Oncology Laboratory, National Cancer Institute; and ² Dipartimento Farmaco-Chimico, University of Bari, Bari, Italy

Requests for reprints: Amalia Azzariti, Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola 209, 70125 Bari, Italy. Phone: 39-80-5555530; Fax: 39-80-5555561. E-mail: amaliaris{at}yahoo.com

Ligands have recently been shown to have cytotoxic activity, to induce ceramide-dependent/caspase-independent apoptosis, and to down-regulate P-glycoprotein (P-gp) mRNA levels in some mouse and human models. In this study, we verified whether a mixed ₂ agonist/₁ antagonist, PB28, was able to have antitumor activity and to enhance anthracycline efficacy in two human breast cancer cell lines, MCF7 and MCF7 ADR, both characterized by significant ₂ receptor expression, by high and low ₁ receptor expression, and low and high P-gp expression, respectively. In both cell lines, PB28 showed high ₂ receptor affinity and low ₁ receptor affinity; furthermore, it inhibited cell growth with a clear effect at 48 hours (IC₅₀ in nanomolar range), a consistent time exposure-independent increase of G₀-G₁-phase fraction (of 20% of both cell lines) and caspase-independent apoptosis (15% increased after 1-day drug exposure). PB28 also reduced P-gp expression in a concentration- and time-dependent manner (60% in MCF7 and 90% in MCF7 ADR). We showed also a strong synergism between PB28 and doxorubicin by adopting either simultaneous or sequential schedules of the two drugs. We suggest that this synergism could depend on PB28-induced increase of intracellular accumulation of doxorubicin (50% in MCF7 and 75% in MCF7 ADR by flow cytometry analysis). In conclusion, we suggest that the ₂ agonist PB28 could be an interesting antitumor agent either in monotherapy or in combination with conventional drugs. [Mol Cancer Ther 2006;5(7):1807–16]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ http://www.clinicaltrials.gov

Received 10/ 4/05; revised 4/20/06; accepted 5/12/06.

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