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.
Highlights
The majority of studies on cellular responses to extracellular stimuli have relied on the use of established, immortalized cells grown as 2-dimensional (2-D) monolayers
Using the spheroidsMARY-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
The limitations of traditional 2-D monolayer cell cultures to predict in vivo response are important in the drug-screening process and may account for the high failure rate and rising costs of drug discovery [40, 41]
Summary
The majority of studies on cellular responses to extracellular stimuli have relied on the use of established, immortalized cells grown as 2-dimensional (2-D) monolayers. 2-D monolayer cultures fail to accurately represent the complex heterogeneous cell-cell interactions as well as the effects of the microenvironment (e.g. hypoxia) typically found in multi-cellular tissue that can modulate gene expression and alter the molecular signaling profile of specific populations of cells [3, 4] These observations have led to the pursuit of three-dimensional (3-D) cell cultures that have the potential to improve the physiological relevance of cell-based studies and increase the successful translation of cell-based drug screening in the discovery of new therapeutics [5,6,7,8]. These methods often generate a limited number of spheroids (e.g. the hanging drop method generates 1 spheroid/well [14]) at a substantial cost, making these systems impractical for high-throughput drug screening and development
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