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Page 10 of 27 J Cancer Metastasis Treat 2019;5:5 I http://dx.doi.org/10.20517/2394-4722.2018.108

Experimental model: Pancreatic cancer xenograft mice were subjected to different dietary approaches such
as intermittent fasting cycles or ERS diet to assess tumor growth as compared to mice fed with a standard
diet. The composition and activity of fecal microbiota and metabolomics profiles were further analyzed by
next generation sequencing (NGS) technology and LC-MS analysis of serum respectively.

Results: Pancreatic cancer cells cultured in fasting mimicking medium and ERS diet-mimicking medium
impacted the proliferation pathway and the nutrients sensitive pathway decreasing the levels of phospho-
ERK1/2 and phospho-mTOR. As compared to those cultured in standard medium. Consistently, xenograft
pancreatic cancer mice subjected to modifies dietary approaches displayed significant retardation in tumor
growth and a significant shift in microbiota profiles towards butyrate producer’s microorganisms.

Conclusion: It is important to modulate dietary habits and apply new dietary intervention in order to
modulate the composition and metabolism of mouse fecal microbiota which is one of the key organs
involved in the chemotherapy response. All these results indicate that engineered dietary interventions may
potentially reveal useful in fighting human cancers and could be supportive as a synergistic approach to
improve the efficacy of existing drugs in pancreatic cancer therapy.

14. Effects of selective targeting of mitochondria in experimental cancer and chemotherapy-
induced cachexia

1,2
1,2
3
Riccardo Ballarò , Marc Beltrà , Paola Costelli , Hazel Szeto , Fabio Penna 1,2
1,2
1 Department of Clinical and Biological Sciences, Experimental Medicine and Clinical Pathology Unit,
University of Turin, Turin 10126, Italy.
2 Interuniversity Institute of Myology, Milano 20132, Italy.
3 Mitochondrial Therapeutics Consulting, New York, NY 10016, USA.

Cachexia is a syndrome frequently occurring in cancer patients. The main features are loss of muscle mass
and function associated with negative energy balance. In this regard, cachectic tumor-bearing animals show
altered mitochondria and reduced oxidative capacity in the muscle. Mitochondrial homeostasis could be
further impaired by chemotherapy administration, contributing to muscle wasting.

The present study aimed at evaluating the effects of a mitochondrial-targeted compound (SS-31) on muscle
wasting in mice bearing the C26 tumor in the presence or in the absence of chemotherapy [oxaliplatin +
fluoruracil (OXFU)].

Reduced body weight, food intake, muscle mass and function were observed in the untreated tumor hosts.
Lifespan in OXFU-treated C26 hosts was almost doubled with respect to untreated animals, however muscle
wasting was exacerbated. SS-31 administration was able to counteract body weight loss, anorexia and the
reduction of myofiber dimensions, while the protection against muscle mass depletion was only slight. As
for markers of mitochondria, both treated and untreated C26 hosts showed that the expression of PGC-1α,
cytochrome c, SDH and cardiolipin levels were reduced compared to control animals, and not modified by
SS-31. In OXFU-treated tumor-bearing mice, also the SDH total activity and ATP content were reduced. SS-
31 increased SDH activity and ATP content in untreated C26 hosts. The modulations of the mitochondrial
compartment in the C26-bearing mice were also associated with markedly decreased protein synthesis, that
improved after administration of SS-31.

In conclusion, these results suggest that targeting mitochondria could be an effective strategy to counteract
cancer cachexia, partially preventing the loss of body weight and food intake, improving muscle
atrophy, muscle oxidative capacity and energy wasting in mice hosting the C26 tumor in the absence of