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.
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: Jolieke G van Oosterwijk; Jacqueline R M Plass; Danielle Meijer; Ivo Que; Marcel Karperien; Judith V M G Bovée Journal: Virchows Arch Date: 2014-10-21 Impact factor: 4.064
Authors: A Italiano; O Mir; A Cioffi; E Palmerini; S Piperno-Neumann; C Perrin; L Chaigneau; N Penel; F Duffaud; J E Kurtz; O Collard; F Bertucci; E Bompas; A Le Cesne; R G Maki; I Ray Coquard; J Y Blay Journal: Ann Oncol Date: 2013-10-07 Impact factor: 32.976
Authors: Yvonne de Jong; Annemiek M van Maldegem; Adrian Marino-Enriquez; Danielle de Jong; Johnny Suijker; Inge H Briaire-de Bruijn; Alwine B Kruisselbrink; Anne-Marie Cleton-Jansen; Karoly Szuhai; Hans Gelderblom; Jonathan A Fletcher; Judith V M G Bovée Journal: Lab Invest Date: 2016-09-12 Impact factor: 5.662
Authors: A Italiano; A Le Cesne; C Bellera; S Piperno-Neumann; F Duffaud; N Penel; P Cassier; J Domont; N Takebe; M Kind; J-M Coindre; J-Y Blay; B Bui Journal: Ann Oncol Date: 2013-11 Impact factor: 32.976