Cytostatic effect of plitidepsin (AplidinTM) in human undifferentiated (anaplastic) thyroid carcinomaCytostatic effect of plitidepsin (AplidinTM) in human undifferentiated (anaplastic) thyroid carcinoma
Susana Bravo1, Maria garcia-renduelles1, Rafael Seoane2, Vanesa Dosil1, Jose Cameselle3, Luis Lopez-Lázaro5, Juan Zalvide1, Franci Barreiro1, Celia Pombo1 & Clara Alvarez1
1Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 2Department of Microbiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 3Department of Pathology, Hospital Clínico Universitario, Santiago de Compostela/Coruña/galicia, Spain , 6Pharma Mar SA, E-28770, Colmenar Viejo, Madrid, Spain , 7Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 8Department of Surgery, Hospital Clínico Universitario, Santiago de Compostela/Coruña/galicia, Spain , 9Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 10Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain.
Undifferentiated thyroid carcinoma is a highly aggressive human cancer with poor prognosis. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations. Plitidepsin (AplidinTM) a novel anticancer compound from a sea tunicate, has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. initiallyexperiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nM plitidepsin induced apoptosis, while lower doses were cytostatic. Since our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were performed with a dosage regime reflecting plasma concentrations observed in previously reported clinical trials: 100 nM for 4 h, followed by 10 nM for 20 h (4100/2010 Plitidepsin). This plitidepsin dosage regime blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis.
The proportion of cells in the G1 phase was greatly increased, and the proportion in the S/G2-M phases greatly reduced, suggesting that plitidepsin blocks G1-to-S transition. Levels of the cyclinD1/cdk4/p21 complex proteins were decreased and levels of unphosphorylated Rb1 increased. Finally, we performed experiments to assess how rapidly tumor cells return to normal behavior after 4100/2010 plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days cell number was still significantly lower than in control cultures. Together, our data show that plitidepsin is able to block in vitro cell-cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established.
Endocrine Abstracts (2006).
Susana Bravo1, Maria garcia-renduelles1, Rafael Seoane2, Vanesa Dosil1, Jose Cameselle3, Luis Lopez-Lázaro5, Juan Zalvide1, Franci Barreiro1, Celia Pombo1 & Clara Alvarez1
1Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 2Department of Microbiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 3Department of Pathology, Hospital Clínico Universitario, Santiago de Compostela/Coruña/galicia, Spain , 6Pharma Mar SA, E-28770, Colmenar Viejo, Madrid, Spain , 7Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 8Department of Surgery, Hospital Clínico Universitario, Santiago de Compostela/Coruña/galicia, Spain , 9Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain , 10Department of Physiology, School of Medicine, Santiago de Compostela/Coruña/galicia, Spain.
Undifferentiated thyroid carcinoma is a highly aggressive human cancer with poor prognosis. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations. Plitidepsin (AplidinTM) a novel anticancer compound from a sea tunicate, has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. initiallyexperiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nM plitidepsin induced apoptosis, while lower doses were cytostatic. Since our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were performed with a dosage regime reflecting plasma concentrations observed in previously reported clinical trials: 100 nM for 4 h, followed by 10 nM for 20 h (4100/2010 Plitidepsin). This plitidepsin dosage regime blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis.
The proportion of cells in the G1 phase was greatly increased, and the proportion in the S/G2-M phases greatly reduced, suggesting that plitidepsin blocks G1-to-S transition. Levels of the cyclinD1/cdk4/p21 complex proteins were decreased and levels of unphosphorylated Rb1 increased. Finally, we performed experiments to assess how rapidly tumor cells return to normal behavior after 4100/2010 plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days cell number was still significantly lower than in control cultures. Together, our data show that plitidepsin is able to block in vitro cell-cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established.
Endocrine Abstracts (2006).