Plitidepsin Has a Cytostatic Effect in Human Undifferentiated (Anaplastic) Thyroid Carcinoma

Abstract

Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive human cancer with very poor prognosis. Although there have been a few studies of candidate treatments, the fact that it is an infrequent tumor makes it very difficult to design clinical trials. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations in numerous molecular genetic and expression studies. Plitidepsin (Aplidin, PharmaMar, Madrid, Spain) is a novel anticancer compound obtained from a sea tunicate.This compound has been reported to induce apoptosis independently of TP53 status.We investigated the actions of plitidepsin in human thyroid cancer cells. In initial experiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that100 nmol/L plitidepsin induced apoptosis, whereas lower doses were cytostatic. Because our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were done with a dosage regimen reflecting plasma concentrations observed in previously reported clinical trials: 100 nmol/L for 4 hours, followed by 10 nmol/L for 20 hours (4 100 /20 10 plitidepsin). This plitidepsin dosage regimen blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) obtained from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis.The proportion of cells in the G 1 phase of the cell cycle was greatly increased and the proportionin the S/G 2 -M phases greatly reduced, suggesting that plitidepsin blocks G 1 -to-S transition. Levels of the cyclin D1/cyclin-dependent kinase 4/p21 complex proteins were decreased and, in line with this, the levels of unphosphorylated Rb1increased.The decrease in cell cycle proteins correlated with hypoacetylation of histone H3. Finally, we did experiments to assess how rapidly tumor cells return to their initial pretreatment proliferative behavior after 4 100 /20 10 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. 4 100 /20 10 plitidepsininhibited the growthin soft agar.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. However, our results raise the possibility that plitidepsin might be effective alone or in combination with radiotherapy and/or other drug treatments.Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive malignant neoplasm typified by rapidly progressive local disease (ref. 1 and references therein). Almost all patients with undifferentiated thyroid carcinoma present...

Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies

“…Bone morphogenetic protein 7 (BMP7), a member of the TGFB1 superfamily, caused growth inhibition in four ATC cell lines by up-regulating p21 cip1 and p27 kip1 , and by inhibiting CDK2 and CDK6 activity and Rb phosphorylation (Franzen & Heldin 2001). Other agents shown to have cytostatic effects on the cell cycle include the marine derived compound plitidepsin (Bravo et al 2005), TP53-expressing adenovirus (Blagosklonny et al 1998), and thiazolidinediones (TZDs) (Podtcheko et al 2003, Aiello et al 2006, Copland et al 2006b, Bonofiglio et al 2008). TZDs exert their growth inhibitory effect via PPARG transcriptional activation, and subsequent p21 activation (Aiello et al 2006, Copland et al 2006b) and involves Sp1 interaction, as it is inhibited by siRNAs to p21 or Sp1, and also by the Sp1 inhibitor, mithramycin (Bonofiglio et al 2008).…”

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells

“…Plitidepsin causes G 1 arrest and G 2 /M blockage in leukemia cells Biscardi et al, 2005). In a recent study, it has been reported that therapeutic concentrations of plitidepsin block anaplastic thyroid carcinoma cells in the G 1 -to-S transition of the cell cycle (Bravo et al, 2005). In contrast, no cell cycle perturbation by plitidepsin has been observed in other human solid tumor cells (García-Ferná ndez et al, 2002;Cuadrado et al, 2003).…”

Personalization of Targeted Therapy in Advanced Thyroid Cancer

“…To date, primary thyroid cancer cell cultures have been obtained from surgical biopsies after therapeutic or diagnostic procedures. Bravo et al [126] reported the establishment of primary cultures by FNA biopsy (FNAB) in 1 patient. However, in patients with thyroid cancer, reports of cutaneous needle track seeding after FNAB have been published [127, 128]; FNA cytology by-passes this problem.…”