Abstract
ViscumTT, a whole mistletoe preparation, has shown synergistic induction of apoptosis in several pediatric tumor entities. High therapeutic potential has previously been observed in Ewing’s sarcoma, rhabdomyosarcoma, ALL and AML. In this study, we analyzed modulatory effects on the cell cycle by viscumTT in three osteosarcoma cell lines with various TP53 statuses. ViscumTT treatment induced G1 arrest in TP53 wild-type and null-mutant cells, but S arrest in TP53 mutant cells. Blockage of G1/S transition was accompanied by down-regulation of the key regulators CDK4, CCND1, CDK2, CCNE, CCNA. However, investigations on the transcriptional level revealed secondary TP53 participation. Cell cycle arrest was predominantly mediated by transcriptionally increased expression of GADD45A and CDKN1A and decreased SKP2 levels. Enhanced CDKN1A and GADD45A expression further played a role in viscumTT-induced apoptosis with involvement of stress-induced MAPK8 and inactivation of MAPK1/3. Furthermore, viscumTT inhibited the pro-survival pathway STAT3 by dephosphorylation of the two sites, Tyr705 and Ser727, by down-regulation of total STAT3 and its direct downstream targets BIRC5 and C-MYC. Moreover, tests of the efficacy of viscumTT in vivo showing reduction of tumor volume confirmed the high therapeutic potential as an anti-tumoral agent for osteosarcoma.
Highlights
ViscumTT is a whole mistletoe extract resulted from combination of two single extracts
Synchronized osteosarcoma cell lines were treated with viscum, TT and viscumTT, and cell cycle distribution was analyzed at different time points
On the basis of our findings, we conclude that GADD45A and cyclin-dependent kinase inhibitor 1 A (CDKN1A) play an important role in viscumTT-mediated action in a Tumor protein 53 (TP53) non-essential manner
Summary
ViscumTT is a whole mistletoe extract resulted from combination of two single extracts (viscum and TT). Viscum represents the aqueous part and is similar to conventional mistletoe preparations It contains mainly hydrophilic mistletoe lectin I (ML I) as well as viscotoxins, whereby ML I is the main active constitutes and functioned as marker substance[1,2]. OA is distinctly higher concentrated in the TT extract and is used as marker substance For both main active constituents of viscumTT, ML I and OA, various anti-tumoral properties such as induction of apoptosis, cell cycle arrest and immunomodulatory functions have been described[6,7,8,9,10,11]. Signal transducer and activator of transcription 3 (STAT3) which is often constitutively activated in diverse tumors[22] was inhibited by a synthetic oleanolic derivative in multi-drug resistant osteosarcoma cells[23] as well as by a fermented mistletoe preparation in gliomas[24]. We demonstrate high therapeutic efficacy of viscumTT in an osteosarcoma xenograft model
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