Parallel assessment of cell viability in cardiac and cancer cells following treatment with sunitinib

Domenica McBride, Abdulfattah Yahya M ALHAZMI, Sarunya Laovitthayanggoon, Marie Boyd, Susan Currie

Research output: Contribution to journalMeeting abstract

Abstract

Various cardiopathological effects have been observed following chemotherapy treatment in cancer patients, due to anti-cancer drug-induced cardiotoxicity (CTX). A retrospective study of cancer survivors reported a 50% and 10% incidence of hypertension and heart failure respectively following treatment with the tyrosine kinase inhibitor sunitinib, licensed to treat pancreatic neuroendocrine tumours. The cellular mechanisms underlying CTX are not known. Here, for the first time, we compare the potency of sunitinib in both cardiac cells (primary cardiac fibroblasts (CFs)) and cancer cells (a pancreatic adenocarcinoma cell line (PANC-1)).

Adult rat CFs were isolated by bulk collagenase digestion, maintained in culture and used between passages 1–2. PANC-1 cells, from previously-frozen stocks, were used between passages 41–49. Cells were treated with sunitinib (0–10 µM in CFs; 0–100 µM in PANC-1) for 24 hour prior to epifluorescent imaging for phenotypic assessment. Cell viability was examined by alamar blue assays following 24 hour sunitinib treatment (0–100 µM).

Overall, results indicated increased sensitivity of CFs to sunitinib compared with PANC-1 cells. Phenotypic changes indicative of cell death, including appearance of intracellular vacuoles, were evident in CFs following 1 µM sunitinib treatment whereas similar effects were not induced until 10 µM treatment in PANC-1 cells. Alamar blue assays demonstrated a dramatic increase in CF death compared to PANC-1 death following treatment with 10 µM sunitinib (11.6±0.02 vs 56.5±1.5 (% viability) CF vs PANC-1, n=3). A lower IC50 value for sunitinib was required to exert the same effects on CF (IC505.2 µM) vs PANC-1 (IC5013.5 µM) cell viability.

These results suggest sunitinib can cause lethal effects in cardiac cells at lower doses than those required to induce pancreatic cancer cell death. Future work will aim to identify cellular mechanisms responsible for these toxic effects. Parallel studies in cardiac and cancer cells will be beneficial in distinguishing how focused anti-cancer drug delivery could be improved to avoid CTX.

Fingerprint

Heart Neoplasms
Cell Survival
Fibroblasts
Therapeutics
Neoplasms
Cell Death
sunitinib
Neuroendocrine Tumors
Poisons
Collagenases
Vacuoles
Pancreatic Neoplasms
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Survivors
Digestion
Adenocarcinoma
Heart Failure
Retrospective Studies

Keywords

  • sunitinib
  • cardiac cells
  • cancer cells

Cite this

@article{a808af8719074fa285cbe47bd6adba8a,
title = "Parallel assessment of cell viability in cardiac and cancer cells following treatment with sunitinib",
abstract = "Various cardiopathological effects have been observed following chemotherapy treatment in cancer patients, due to anti-cancer drug-induced cardiotoxicity (CTX). A retrospective study of cancer survivors reported a 50{\%} and 10{\%} incidence of hypertension and heart failure respectively following treatment with the tyrosine kinase inhibitor sunitinib, licensed to treat pancreatic neuroendocrine tumours. The cellular mechanisms underlying CTX are not known. Here, for the first time, we compare the potency of sunitinib in both cardiac cells (primary cardiac fibroblasts (CFs)) and cancer cells (a pancreatic adenocarcinoma cell line (PANC-1)).Adult rat CFs were isolated by bulk collagenase digestion, maintained in culture and used between passages 1–2. PANC-1 cells, from previously-frozen stocks, were used between passages 41–49. Cells were treated with sunitinib (0–10 µM in CFs; 0–100 µM in PANC-1) for 24 hour prior to epifluorescent imaging for phenotypic assessment. Cell viability was examined by alamar blue assays following 24 hour sunitinib treatment (0–100 µM).Overall, results indicated increased sensitivity of CFs to sunitinib compared with PANC-1 cells. Phenotypic changes indicative of cell death, including appearance of intracellular vacuoles, were evident in CFs following 1 µM sunitinib treatment whereas similar effects were not induced until 10 µM treatment in PANC-1 cells. Alamar blue assays demonstrated a dramatic increase in CF death compared to PANC-1 death following treatment with 10 µM sunitinib (11.6±0.02 vs 56.5±1.5 ({\%} viability) CF vs PANC-1, n=3). A lower IC50 value for sunitinib was required to exert the same effects on CF (IC505.2 µM) vs PANC-1 (IC5013.5 µM) cell viability.These results suggest sunitinib can cause lethal effects in cardiac cells at lower doses than those required to induce pancreatic cancer cell death. Future work will aim to identify cellular mechanisms responsible for these toxic effects. Parallel studies in cardiac and cancer cells will be beneficial in distinguishing how focused anti-cancer drug delivery could be improved to avoid CTX.",
keywords = "sunitinib, cardiac cells, cancer cells",
author = "Domenica McBride and ALHAZMI, {Abdulfattah Yahya M} and Sarunya Laovitthayanggoon and Marie Boyd and Susan Currie",
year = "2018",
month = "3",
day = "26",
doi = "10.1136/heartjnl-2018-SCF.16",
language = "English",
volume = "104",
journal = "Heart",
issn = "1355-6037",
number = "S4",

}

Parallel assessment of cell viability in cardiac and cancer cells following treatment with sunitinib. / McBride, Domenica; ALHAZMI, Abdulfattah Yahya M; Laovitthayanggoon, Sarunya; Boyd, Marie; Currie, Susan.

In: Heart , Vol. 104, No. S4, 6, 26.03.2018.

Research output: Contribution to journalMeeting abstract

TY - JOUR

T1 - Parallel assessment of cell viability in cardiac and cancer cells following treatment with sunitinib

AU - McBride, Domenica

AU - ALHAZMI, Abdulfattah Yahya M

AU - Laovitthayanggoon, Sarunya

AU - Boyd, Marie

AU - Currie, Susan

PY - 2018/3/26

Y1 - 2018/3/26

N2 - Various cardiopathological effects have been observed following chemotherapy treatment in cancer patients, due to anti-cancer drug-induced cardiotoxicity (CTX). A retrospective study of cancer survivors reported a 50% and 10% incidence of hypertension and heart failure respectively following treatment with the tyrosine kinase inhibitor sunitinib, licensed to treat pancreatic neuroendocrine tumours. The cellular mechanisms underlying CTX are not known. Here, for the first time, we compare the potency of sunitinib in both cardiac cells (primary cardiac fibroblasts (CFs)) and cancer cells (a pancreatic adenocarcinoma cell line (PANC-1)).Adult rat CFs were isolated by bulk collagenase digestion, maintained in culture and used between passages 1–2. PANC-1 cells, from previously-frozen stocks, were used between passages 41–49. Cells were treated with sunitinib (0–10 µM in CFs; 0–100 µM in PANC-1) for 24 hour prior to epifluorescent imaging for phenotypic assessment. Cell viability was examined by alamar blue assays following 24 hour sunitinib treatment (0–100 µM).Overall, results indicated increased sensitivity of CFs to sunitinib compared with PANC-1 cells. Phenotypic changes indicative of cell death, including appearance of intracellular vacuoles, were evident in CFs following 1 µM sunitinib treatment whereas similar effects were not induced until 10 µM treatment in PANC-1 cells. Alamar blue assays demonstrated a dramatic increase in CF death compared to PANC-1 death following treatment with 10 µM sunitinib (11.6±0.02 vs 56.5±1.5 (% viability) CF vs PANC-1, n=3). A lower IC50 value for sunitinib was required to exert the same effects on CF (IC505.2 µM) vs PANC-1 (IC5013.5 µM) cell viability.These results suggest sunitinib can cause lethal effects in cardiac cells at lower doses than those required to induce pancreatic cancer cell death. Future work will aim to identify cellular mechanisms responsible for these toxic effects. Parallel studies in cardiac and cancer cells will be beneficial in distinguishing how focused anti-cancer drug delivery could be improved to avoid CTX.

AB - Various cardiopathological effects have been observed following chemotherapy treatment in cancer patients, due to anti-cancer drug-induced cardiotoxicity (CTX). A retrospective study of cancer survivors reported a 50% and 10% incidence of hypertension and heart failure respectively following treatment with the tyrosine kinase inhibitor sunitinib, licensed to treat pancreatic neuroendocrine tumours. The cellular mechanisms underlying CTX are not known. Here, for the first time, we compare the potency of sunitinib in both cardiac cells (primary cardiac fibroblasts (CFs)) and cancer cells (a pancreatic adenocarcinoma cell line (PANC-1)).Adult rat CFs were isolated by bulk collagenase digestion, maintained in culture and used between passages 1–2. PANC-1 cells, from previously-frozen stocks, were used between passages 41–49. Cells were treated with sunitinib (0–10 µM in CFs; 0–100 µM in PANC-1) for 24 hour prior to epifluorescent imaging for phenotypic assessment. Cell viability was examined by alamar blue assays following 24 hour sunitinib treatment (0–100 µM).Overall, results indicated increased sensitivity of CFs to sunitinib compared with PANC-1 cells. Phenotypic changes indicative of cell death, including appearance of intracellular vacuoles, were evident in CFs following 1 µM sunitinib treatment whereas similar effects were not induced until 10 µM treatment in PANC-1 cells. Alamar blue assays demonstrated a dramatic increase in CF death compared to PANC-1 death following treatment with 10 µM sunitinib (11.6±0.02 vs 56.5±1.5 (% viability) CF vs PANC-1, n=3). A lower IC50 value for sunitinib was required to exert the same effects on CF (IC505.2 µM) vs PANC-1 (IC5013.5 µM) cell viability.These results suggest sunitinib can cause lethal effects in cardiac cells at lower doses than those required to induce pancreatic cancer cell death. Future work will aim to identify cellular mechanisms responsible for these toxic effects. Parallel studies in cardiac and cancer cells will be beneficial in distinguishing how focused anti-cancer drug delivery could be improved to avoid CTX.

KW - sunitinib

KW - cardiac cells

KW - cancer cells

UR - http://heart.bmj.com/content/104/Suppl_4/A6.3

U2 - 10.1136/heartjnl-2018-SCF.16

DO - 10.1136/heartjnl-2018-SCF.16

M3 - Meeting abstract

VL - 104

JO - Heart

T2 - Heart

JF - Heart

SN - 1355-6037

IS - S4

M1 - 6

ER -