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

Abstract Background The 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 result...

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Main Authors: M. V. Sheraton, G. G. Y. Chiew, V. Melnikov, E. Y. Tan, K. Q. Luo, N. Verma, P. M. A. Sloot
Format: Article
Language:English
Published: BMC 2020-12-01
Series:BMC Cancer
Subjects:
Online Access:https://doi.org/10.1186/s12885-020-07677-5
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author M. V. Sheraton
G. G. Y. Chiew
V. Melnikov
E. Y. Tan
K. Q. Luo
N. Verma
P. M. A. Sloot
author_facet M. V. Sheraton
G. G. Y. Chiew
V. Melnikov
E. Y. Tan
K. Q. Luo
N. Verma
P. M. A. Sloot
author_sort M. V. Sheraton
collection DOAJ
description Abstract Background The 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. Methods 3D 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. Results The 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. Conclusions The 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.
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spelling doaj.art-0086e308a20943f0919d1e0d0483a23f2022-12-21T23:21:32ZengBMCBMC Cancer1471-24072020-12-0120111610.1186/s12885-020-07677-5Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studiesM. V. Sheraton0G. G. Y. Chiew1V. Melnikov2E. Y. Tan3K. Q. Luo4N. Verma5P. M. A. Sloot6HEALTHTECH NTU, Interdisciplinary Graduate School, Nanyang Technological UniversitySchool of Chemical and Biomedical Engineering, Nanyang Technological UniversityComplexity Institute, Nanyang Technological UniversityDepartment of General Surgery, Tan Tock Seng HospitalFaculty of Health Sciences, University of MacauDepartment of Chemical Engineering, Indian Institute of Technology KanpurComplexity Institute, Nanyang Technological UniversityAbstract Background The 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. Methods 3D 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. Results The 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. Conclusions The 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.https://doi.org/10.1186/s12885-020-07677-5Reaction-diffusion modelPharmacokineticsPharmacodynamicsMitotic spindle stabilizationCytotoxicity
spellingShingle M. V. Sheraton
G. G. Y. Chiew
V. Melnikov
E. Y. Tan
K. Q. Luo
N. Verma
P. M. A. Sloot
Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
BMC Cancer
Reaction-diffusion model
Pharmacokinetics
Pharmacodynamics
Mitotic spindle stabilization
Cytotoxicity
title Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
title_full Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
title_fullStr Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
title_full_unstemmed Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
title_short Emergence of spatio-temporal variations in chemotherapeutic drug efficacy: in-vitro and in-Silico 3D tumour spheroid studies
title_sort emergence of spatio temporal variations in chemotherapeutic drug efficacy in vitro and in silico 3d tumour spheroid studies
topic Reaction-diffusion model
Pharmacokinetics
Pharmacodynamics
Mitotic spindle stabilization
Cytotoxicity
url https://doi.org/10.1186/s12885-020-07677-5
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