title: Cyclohexylpiperazine derivative PB28, a sigma2 agonist and sigma1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer.
abstract: sigma 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 sigma(2) agonist/sigma(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 sigma(2) receptor expression, by high and low sigma(1) receptor expression, and low and high P-gp expression, respectively. In both cell lines, PB28 showed high sigma(2) receptor affinity and low sigma(1) receptor affinity; furthermore, it inhibited cell growth with a clear effect at 48 hours (IC(50) in nanomolar range), a consistent time exposure-independent increase of G(0)-G(1)-phase fraction (of approximately 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 ( approximately 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 ( approximately 50% in MCF7 and 75% in MCF7 ADR by flow cytometry analysis). In conclusion, we suggest that the sigma(2) agonist PB28 could be an interesting antitumor agent either in monotherapy or in combination with conventional drugs.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola 209, 70125 Bari, Italy. amaliaris@yahoo.com
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Simone
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D000970:Antineoplastic Agents; D003630:Daunorubicin; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C513937:PB28 compound; C106107:sigma-2 receptor