Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies

M. V. Sheraton,K. Q. Luo,E. Y. Tan,G. G. Y. Chiew,P. M. A. Sloot,N. Verma,V. Melnikov

doi:10.1186/s12885-020-07677-5

Abstract

BackgroundThe mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, however the localized spatio-temporal effects of the drugs are less well understood. We explore the emergence of spatially preferential drug efficacy resulting from variations in mechanisms of cell-drug interactions.Methods3D spheroids of HeLa-C3 cells were treated with drugs, cisplatin and paclitaxel. This was followed by sectioning and staining of the spheroids to track the spatio-temporal apoptotic effects of the drugs. A mechanistic drug-cell interaction model was developed and simulated to analyse the localized efficacy of these drugs.ResultsThe outcomes of drug actions on a local cell population was dependant on the interactions between cell repair probability, intracellular drug concentration and cell’s mitosis phase. In spheroids treated with cisplatin, drug induced apoptosis is found to be scattered throughout the volume of the spheroids. In contrast, effect of paclitaxel is found to be preferentially localized along the periphery of the spheroids. Combinatorial treatments of cisplatin and paclitaxel result in varying levels of cell apoptosis based on the scheduling strategy.ConclusionsThe preferential action of paclitaxel can be attributed to the cell characteristics of the peripheral population. The model simulations and experimental data show that treatments initiated with paclitaxel are more efficacious due to the cascading of spatial effects of the drugs.

Highlights

The mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, the localized spatio-temporal effects of the drugs are less well understood
In this study, we examined the drug response of human cervical cancer HeLa-C3 cell spheroids to the combinatorial administration of two first line anti-cancer drugscisplatin and Taxol. Three dimensional (3D) spheroids were employed in our studies instead of Two dimensional (2D) cell culture experiments to capture the spatial mass-transfer kinetics and cell growth dynamics
The capability of cisplatin is to influence the entire volume of the spheroid limited by the cell DNA repair mechanism

Summary

Introduction

The mechanisms of action and efficacy of cisplatin and paclitaxel at cell population level are well studied and documented, the localized spatio-temporal effects of the drugs are less well understood. 3D spheroid models have been able to replicate the features of in-vivo tumour, such as activation of pathways upon cell-cell interactions [1], presence of concentration gradients within the tumour, and heterogenous microenvironment which can alter pharmacokinetics (PK) of the chemotherapeutic drug [2]. These systems provide a clear advantage over the classical monolayer or 2D culture systems which do not resemble the in-vivo conditions of tumour growth. By combining the device with flow cytometry, it was possible to conduct drug testing and analysis on the formed 3D spheroids. It should be possible to observe in real time the cells in the different stages of their life cycles at different layers inside the spheroid

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Conclusion