title: Spontaneously-forming spheroids as an in vitro cancer cell model for anticancer drug screening.
abstract: The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 μM for gambogic acid and 0.66 +/-0.02 μM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 μM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore.
authors.affiliation: Department of Biology, Arcadia University, Philadelphia, PA, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Theodoraki
authors.affiliation: Department of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.
authors.forename: Celso O
authors.initials: CO
authors.lastname: Rezende
authors.affiliation: Department of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.|Department of Chemistry, Faculty of Science, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
authors.forename: Oraphin
authors.initials: O
authors.lastname: Chantarasriwong
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Adriana D
authors.initials: AD
authors.lastname: Corben
authors.affiliation: Department of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
authors.affiliation: Department of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.|Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Alpaugh
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D029760:Garcinia / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D018874:Spheroids, Cellular / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D044004:Xanthones / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C052659:gambogic acid
keywords: breast cancer; drug screening; garcinia xanthone motif (CGX); lymphovascular embolus (LVE); natural products