Spontaneously-forming spheroids as anin vitrocancer cell model for anticancer drug screening

// Maria A. Theodoraki 1 , Celso O. Rezende Jr. 2 , Oraphin Chantarasriwong 2, 3 , Adriana D. Corben 4 , Emmanuel A. Theodorakis 2 and Mary L. Alpaugh 2, 5 1 Department of Biology, Arcadia University, Philadelphia, PA, USA 2 Department of Chemistry and Biochemistry, University of California – San Diego, La Jolla, CA, USA 3 Department of Chemistry, Faculty of Science, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand 4 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Mary L. Alpaugh, e-mail: alpaughm@mskcc.org Emmanuel A. Theodorakis, e-mail: etheodor@ucsd.edu Keywords: drug screening, lymphovascular embolus (LVE), natural products, garcinia xanthone motif (CGX), breast cancer Received: February 16, 2015      Accepted: June 08, 2015      Published: June 18, 2015 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 IC 50 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 IC 50 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 IC 50 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.