Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells

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Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells. / Sheard, Jonathan J.; Southam, Andrew D.; MacKay, Hannah L.; Ellington, Max A.; Snow, Martyn D.; Khanim, Farhat L.; Bunce, Christopher M.; Johnson, William E.

In: Bioscience Reports, Vol. 41, No. 1, BSR20202505, 29.01.2021.

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@article{42852a64d6fa44f1805317ffbf1ef4ff,
title = "Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells",
abstract = "Drug repurposing is a cost-effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts.",
keywords = "cell death, cell proliferation, drug repurposing, mesenchymal stem cell, osteosarcoma",
author = "Sheard, {Jonathan J.} and Southam, {Andrew D.} and MacKay, {Hannah L.} and Ellington, {Max A.} and Snow, {Martyn D.} and Khanim, {Farhat L.} and Bunce, {Christopher M.} and Johnson, {William E.}",
note = "Funding Information: This study was funded by the BBSRC [grant number BB/H016570/1 to J.J.S. and W.E.J.] and by Blood Cancer U.K. (to F.L.K. and C.M.B.). Publisher Copyright: {\textcopyright} 2021 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).",
year = "2021",
month = jan,
day = "29",
doi = "10.1042/BSR20202505",
language = "English",
volume = "41",
journal = "Bioscience Reports",
issn = "0144-8463",
publisher = "Portland Press",
number = "1",

}

RIS

TY - JOUR

T1 - Combined bezafibrate, medroxyprogesterone acetate and valproic acid treatment inhibits osteosarcoma cell growth without adversely affecting normal mesenchymal stem cells

AU - Sheard, Jonathan J.

AU - Southam, Andrew D.

AU - MacKay, Hannah L.

AU - Ellington, Max A.

AU - Snow, Martyn D.

AU - Khanim, Farhat L.

AU - Bunce, Christopher M.

AU - Johnson, William E.

N1 - Funding Information: This study was funded by the BBSRC [grant number BB/H016570/1 to J.J.S. and W.E.J.] and by Blood Cancer U.K. (to F.L.K. and C.M.B.). Publisher Copyright: © 2021 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

PY - 2021/1/29

Y1 - 2021/1/29

N2 - Drug repurposing is a cost-effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts.

AB - Drug repurposing is a cost-effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts.

KW - cell death

KW - cell proliferation

KW - drug repurposing

KW - mesenchymal stem cell

KW - osteosarcoma

UR - http://www.scopus.com/inward/record.url?scp=85099169395&partnerID=8YFLogxK

U2 - 10.1042/BSR20202505

DO - 10.1042/BSR20202505

M3 - Article

C2 - 33289496

AN - SCOPUS:85099169395

VL - 41

JO - Bioscience Reports

JF - Bioscience Reports

SN - 0144-8463

IS - 1

M1 - BSR20202505

ER -