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Updated: Mar 15, 2026
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Targeting HSP70 and GRP78 in canine osteosarcoma cells in combination with doxorubicin chemotherapy
Jonathan Asling1, Jodi Morrison1, Anthony J Mutsaers2,3
1Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
Abstract:
Heat shock proteins (HSPs) are molecular chaperones subdivided into several families based on their molecular weight. Due to their cytoprotective roles, these proteins may help protect cancer cells against chemotherapy-induced cell death. Investigation into the biologic activity of HSPs in a variety of cancers including primary bone tumors, such as osteosarcoma (OSA), is of great interest. Both human and canine OSA tumor samples have aberrant production of HSP70. This study assessed the response of canine OSA cells to inhibition of HSP70 and GRP78 by the ATP-mimetic VER-155008 and whether this treatment strategy could sensitize cells to doxorubicin chemotherapy. Single-agent VER-155008 treatment decreased cellular viability and clonogenic survival and increased apoptosis in canine OSA cell lines. However, combination schedules with doxorubicin after pretreatment with VER-155008 did not improve inhibition of cellular viability, apoptosis, or clonogenic survival. Treatment with VER-155008 prior to chemotherapy resulted in an upregulation of target proteins HSP70 and GRP78 in addition to the co-chaperone proteins Herp, C/EBP homologous transcription protein (CHOP), and BAG-1. The increased GRP78 was more cytoplasmic in location compared to untreated cells. Single-agent treatment also revealed a dose-dependent reduction in activated and total Akt. Based on these results, targeting GRP78 and HSP70 may have biologic activity in canine osteosarcoma. Further studies are required to determine if and how this strategy may impact the response of osteosarcoma cells to chemotherapy.
Insights
Inhibiting heat shock proteins (HSPs) like HSP70 and GRP78 showed anti-cancer effects in canine osteosarcoma cells. However, combining this with doxorubicin did not enhance chemotherapy outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Heat shock proteins (HSPs) are molecular chaperones with cytoprotective functions.
- Aberrant production of HSP70 is observed in both human and canine osteosarcoma (OSA).
- HSPs may protect cancer cells from chemotherapy-induced death, making them potential therapeutic targets.
Purpose of the Study:
- To assess the anti-cancer effects of inhibiting HSP70 and GRP78 in canine OSA cells using VER-155008.
- To determine if HSP70 and GRP78 inhibition can sensitize canine OSA cells to doxorubicin chemotherapy.
- To investigate the molecular response of canine OSA cells to VER-155008 treatment.
Main Methods:
- Canine OSA cell lines were treated with the ATP-mimetic VER-155008, alone and in combination with doxorubicin.
- Cellular viability, clonogenic survival, and apoptosis were assessed.
- Protein expression levels of HSP70, GRP78, and related chaperones/signaling molecules were analyzed via Western blot.
Main Results:
- Single-agent VER-155008 decreased cellular viability, clonogenic survival, and increased apoptosis in canine OSA cells.
- Combination therapy with doxorubicin did not improve outcomes compared to single-agent VER-155008.
- VER-155008 treatment led to upregulation of HSP70, GRP78, Herp, CHOP, and BAG-1, with increased cytoplasmic GRP78.
- Single-agent VER-155008 also caused a dose-dependent reduction in activated and total Akt.
Conclusions:
- Targeting GRP78 and HSP70 demonstrates biologic activity in canine osteosarcoma.
- The combination strategy with doxorubicin did not enhance chemotherapy efficacy in this model.
- Further research is needed to elucidate the precise role of HSP70 and GRP78 inhibition in osteosarcoma treatment and chemotherapy response.
