Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance.

Abstract

BACKGROUND:

Chondrosarcomas are malignant cartilage-forming tumors notorious for their resistance to conventional chemo- and radiotherapy. Postulated explanations describe the inaccessibility due to abundant hyaline cartilaginous matrix, presence of multidrug resistance (MDR) pumps, and expression of anti-apoptotic BCL-2 family members.

MATERIALS AND METHODS:

We studied the sensitivity of chondrosarcoma cell lines (SW1353, CH2879, JJ012, OUMS27) and two primary cultures for doxorubicin and cisplatin. We examined the role of extracellular matrix using three-dimensional (3D) pellet models and MDR pump activity using fluorescence-activated cell sorter analysis. The role of BCL-2 family members was investigated using the BH3 mimetic ABT-737.

RESULTS:

Chondrosarcoma cells showed highest resistance to cisplatin. 3D cell pellets, morphologically strongly resembling chondrosarcoma in vivo, confirmed nuclear incorporation of doxorubicin. MDR pump activity was heterogeneous among cultures. Chondrosarcoma cells responded to ABT-737 and combination with doxorubicin led to complete loss of cell viability and apoptosis with cytochrome C release.

CONCLUSIONS:

Despite MDR pump activity and abundance of hyaline cartilaginous matrix, doxorubicin is able to accumulate in the cell nuclei. By repairing the apoptotic machinery, we were able to sensitize chondrosarcoma cells to doxorubicin and cisplatin, indicating an important role for BCL-2 family members in chemoresistance and a promising new treatment strategy for inoperable chondrosarcoma.

• Authors: J G van Oosterwijk, B Herpers, D Meijer, I H Briaire-de Bruijn, A M Cleton-Jansen, H Gelderblom, B van de Water, J V M G Bovée
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 23 Issue 6 Pg. 1617-26 (Jun 2012) ISSN: 1569-8041 [Electronic] England
• PMID: 22112972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ABT-737
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Biphenyl Compounds
• Multidrug Resistance-Associated Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• bcl-X Protein
• Doxorubicin
• Cisplatin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacology)
• Cell Culture Techniques
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Chondrosarcoma
• Cisplatin (pharmacology)
• Dose-Response Relationship, Drug
• Doxorubicin (metabolism, pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Gene Expression
• HL-60 Cells
• Humans
• Inhibitory Concentration 50
• Multidrug Resistance-Associated Proteins (metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (metabolism)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology)
• bcl-X Protein (genetics, metabolism)