title: The combination of thioxodihydroquinazolinones and platinum drugs reverses platinum resistance in tumor cells by inducing mitochondrial apoptosis independent of Bax and Bak.
abstract: The effective management of tumors resistant to platinum drugs-based anticancer therapies is a critical challenge in current clinical practices. The proapoptotic Bcl-2 family proteins Bax and Bak are essential for cisplatin-induced apoptosis. Unfortunately, Bax and its related upstream endogenous apoptotic signaling pathways are often dysregulated in cancer cells. Strategies that are able to bypass Bax- and Bak-dependent apoptotic pathways will thus provide opportunities to overcome platinum drug resistance. We have identified the thioxodihydroquinazolinone mdivi-1 as a member of a novel class of small molecules that are able to induce Bax- and Bak-independent mitochondrial outer membrane permeabilization when combined with cisplatin, thereby efficiently triggering apoptosis in platinum-resistant tumor cells. In the present structure activity relationship (SAR) study of a computationally selected library of mdivi-1 related small molecules, we established a pharmacophore model that can lead to the enhancement of platinum drug efficacy and Bax/Bak-independent mitochondrial apoptosis. Specifically, we found that a thiourea function is necessary but not sufficient for the synergism of this class of thioxodihydroquinazolinones with cisplatin. We were also able to identify more potent mdivi-1 analogs through this SAR study, which will guide future designs with the goal to develop novel combination regimens for the treatment of platinum- and multidrug-resistant tumors.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, United States. Electronic address: qianw@upmc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Salamoun
authors.affiliation: Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, United States.
authors.forename: Vera
authors.initials: V
authors.lastname: Roginskaya
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, and Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA 15213, United States.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States; Center for Chemical Methodologies and Library Development, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States. Electronic address: pwipf@pitt.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D009944:Organoplatinum Compounds; D052999:Quinazolinones; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: Bax/Bak-independent apoptosis; Cisplatin; Mdivi-1; Platinum drug resistance; Thioxodihydroquinazolinone