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

1
Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy
2
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
3
Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
4
Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
5
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy
6
Dipartimento di Medicina Veterinaria, Università di Milano, 20133 Milan, Italy
7
Mouse and Animal Pathology Lab (MAPLab), Fondazione UniMi, Università di Milano, 20139 Milan, Italy
8
Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(8), 2312; https://doi.org/10.3390/cancers12082312
Received: 13 July 2020 / Revised: 31 July 2020 / Accepted: 11 August 2020 / Published: 17 August 2020
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. View Full-Text
Keywords: cancer cachexia; muscle atrophy; lurbinectedin; trabectedin; inflammation; splenomegaly cancer cachexia; muscle atrophy; lurbinectedin; trabectedin; inflammation; splenomegaly
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MDPI and ACS Style

Aquila, G.; Re Cecconi, A.D.; Forti, M.; Frapolli, R.; Bello, E.; Novelli, D.; Russo, I.; Licandro, S.A.; Staszewsky, L.; Martinelli, G.B.; Talamini, L.; Pasetto, L.; Resovi, A.; Giavazzi, R.; Scanziani, E.; Careccia, G.; Vénéreau, E.; Masson, S.; Latini, R.; D'Incalci, M.; Piccirillo, R. Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia. Cancers 2020, 12, 2312. https://doi.org/10.3390/cancers12082312

AMA Style

Aquila G, Re Cecconi AD, Forti M, Frapolli R, Bello E, Novelli D, Russo I, Licandro SA, Staszewsky L, Martinelli GB, Talamini L, Pasetto L, Resovi A, Giavazzi R, Scanziani E, Careccia G, Vénéreau E, Masson S, Latini R, D'Incalci M, Piccirillo R. Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia. Cancers. 2020; 12(8):2312. https://doi.org/10.3390/cancers12082312

Chicago/Turabian Style

Aquila, Giorgio, Andrea David Re Cecconi, Mara Forti, Roberta Frapolli, Ezia Bello, Deborah Novelli, Ilaria Russo, Simonetta Andrea Licandro, Lidia Staszewsky, Giulia Benedetta Martinelli, Laura Talamini, Laura Pasetto, Andrea Resovi, Raffaella Giavazzi, Eugenio Scanziani, Giorgia Careccia, Emilie Vénéreau, Serge Masson, Roberto Latini, Maurizio D'Incalci, and Rosanna Piccirillo. 2020. "Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia" Cancers 12, no. 8: 2312. https://doi.org/10.3390/cancers12082312

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