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Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.

ABSTRACT: Receptor tyrosine kinases (RTKs) inhibitors' activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.

SUBMITTER: Chiabotto G

PROVIDER: S-EPMC7352822 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.

Chiabotto Giulia G Grignani Giovanni G Todorovic Maja M Martin Valentina V Centomo Maria Laura ML Prola Elisa E Giordano Giorgia G Merlini Alessandra A Miglio Umberto U Berrino Enrico E Napione Lucia L Isella Claudio C Capozzi Federica F Basiricò Marco M Marsero Cristina C Gerardi Ilaria I Venesio Tiziana T Sangiolo Dario D Aglietta Massimo M D'Ambrosio Lorenzo L Pignochino Ymera Y

Cancers 20200610 6

Receptor tyrosine kinases (RTKs) inhibitors' activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K ...[more]

PMID: 32531992

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Project description:The constant, ever-increasing antibiotic resistance crisis leads to the announcement of "urgent, novel antibiotics needed" by the World Health Organization. Our previous works showed a promising synergistic antibacterial activity of silver nitrate with potassium tellurite out of thousands of other metal/metalloid-based antibacterial combinations. The silver-tellurite combined treatment not only is more effective than common antibiotics but also prevents bacterial recovery, decreases the risk of future resistance chance, and decreases the effective concentrations. We demonstrate that the silver-tellurite combination is effective against clinical isolates. Further, this study was conducted to address knowledge gaps in the available data on the antibacterial mechanism of both silver and tellurite, as well as to give insight into how the mixture provides synergism as a combination. Here, we defined the differentially expressed gene profile of Pseudomonas aeruginosa under silver, tellurite, and silver-tellurite combination stress using an RNA sequencing approach to examine the global transcriptional changes in the challenged cultures grown in simulated wound fluid. The study was complemented with metabolomics and biochemistry assays. Both metal ions mainly affected four cellular processes, including sulfur homeostasis, reactive oxygen species response, energy pathways, and the bacterial cell membrane (for silver). Using a Caenorhabditis elegans animal model we showed silver-tellurite has reduced toxicity over individual metal/metalloid salts and provides increased antioxidant properties to the host. This work demonstrates that the addition of tellurite would improve the efficacy of silver in biomedical applications. IMPORTANCE Metals and/or metalloids could represent antimicrobial alternatives for industrial and clinical applications (e.g., surface coatings, livestock, and topical infection control) because of their great properties, such as good stability and long half-life. Silver is the most common antimicrobial metal, but resistance prevalence is high, and it can be toxic to the host above a certain concentration. We found that a silver-tellurite composition has antibacterial synergistic effect and that the combination is beneficial to the host. So, the efficacy and application of silver could increase by adding tellurite in the recommended concentration(s). We used different methods to evaluate the mechanism for how this combination can be so incredibly synergistic, leading to efficacy against antibiotic- and silver-resistant isolates. Our two main findings are that (i) both silver and tellurite mostly target the same pathways and (ii) the coapplication of silver with tellurite tends not to target new pathways but targets the same pathways with an amplified change.

Dataset Information

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.

Publications

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.

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