title: Honokiol synergizes chemotherapy drugs in multidrug resistant breast             cancer cells via enhanced apoptosis and additional programmed necrotic death.
abstract: Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety of human cancer cells through apoptosis and other forms of programmed cell death (such as programmed necrosis). Although much work has been done on its antitumor effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drug‑resistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 µg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factor‑κB (NF-κB) activation. Our data for the first time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.
authors.affiliation: Department of Surgical Oncology, The Second Affiliated Hospital,                     School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R.                     China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Yongchuan
authors.initials: Y
authors.lastname: Deng
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Haifei
authors.initials: H
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D017705:Lignans / Q000008:administration & dosage*; D061986:MCF-7 Cells; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D005047:Etoposide; D017705:Lignans; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols