Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia

Author:

Aquila GiorgioORCID,Re Cecconi Andrea DavidORCID,Forti Mara,Frapolli Roberta,Bello Ezia,Novelli Deborah,Russo IlariaORCID,Licandro Simonetta Andrea,Staszewsky Lidia,Martinelli Giulia Benedetta,Talamini Laura,Pasetto Laura,Resovi Andrea,Giavazzi Raffaella,Scanziani Eugenio,Careccia GiorgiaORCID,Vénéreau Emilie,Masson Serge,Latini Roberto,D'Incalci Maurizio,Piccirillo RosannaORCID

Abstract

Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory cytokines and subsequent splenomegaly. We tested whether such drugs protected these mice from cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg ET743 or 0.07 mg/kg PM01183, three times a week for three weeks. ET743 or PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from cachexia. Since PM01183 extended the animal survival more than ET743, we analyzed PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes, PM01183 restrained the NF-κB/PAX7/myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBPβ/atrogin-1 axis. Inflammation-mediated splenomegaly of C26-mice was inhibited by PM01183 for as long as the treatment lasted, without reducing IL-6, M-CSF or IL-1β in plasma. ET743 and PM01183 extend the survival of C26-bearing mice unchanging tumor growth or cachexia but possibly restrain muscle-related inflammation and C26-induced splenomegaly.

Funder

Associazione Italiana per la Ricerca sul Cancro

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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