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Page 23 of 36 J Cancer Metastasis Treat 2019;5:31 I http://dx.doi.org/10.20517/2394-4722.2019.21

mediated by both these mechanisms. Moreover, treatment of CRPC cells with salubrinal impairs d-TT-
induced LC3-II expression, demonstrating that this compound triggers the ER stress-autophagy axis; (2) in
CRPC cells, the expression levels of the proteins of the respiratory chain complexes are increased compared
to non-tumoral cells, supporting a reprogramming of the OXPHOS system. In these cells, d-TT: decreases
the expression levels of the proteins of the respiratory chain complexes, specifically of complex I; decreases
the mitochondrial activity as well as the mitochondrial activity/mass ratio; decreases both ATP production
and oxygen consumption. These data demonstrate that d-TT exerts a significant proapoptotic activity in
CRPC cells through activation of the ER stress-autophagy axis and rewiring of mitochondrial metabolism.

Biography
Patrizia Limonta has completed her post-graduate degrees in Pharmacology and in Experimental
Endocrinology. She is full professor of Applied Biology at the Department of Pharmacological and
Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy. She has published more than
90 papers in reputed journals and has been serving as an editorial board member of Frontiers in
Endocrinology (Cancer Endocrinology Section), Recent Patents in Anticancer Drug Discovery, Oncology
Letters, Clinical Cancer Drugs.

29. Targeting metabolic dysfunction in cancer cells by combinatorial treatment with natural
compounds

1
1
2
1
1
Alessia Lodi , Achinto Saha , Xi-Yuan Lu1, Bo Wang , Enrique Sentandreu , Meghan Collins , Mikhail G.
Kolonin , John DiGiovanni , Stefano Tiziani 1,4
3
2,4
1 Department of Nutritional Sciences, University of Texas at Austin, Austin, TX 78712, USA.
2 Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX
78712, USA.
3 The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at
Houston, Houston, TX 77030, USA.
4 Dell Pediatric Research Institute, University of Texas at Austin, Austin, TX 78712, USA.

Natural compounds ingested through the diet can modulate key molecular signaling, inhibit cancer
cell proliferation and induce apoptosis. According to the World Health Organization, an increased
consumption of natural compounds could prevent about one-third of all cancer deaths. Libraries of natural
compounds incorporate phytochemicals characterized by vast molecular diversity and are essential to
identify combinations that synergistically contribute to improving treatment outcome. Given the very
large number of possible combinations, high-throughput screening methods are paramount to identify
the most efficacious compound combinations. In this study, we used high-throughput screening to test
the outcome of natural compound combinations on prostate cancer. The in vitro screen identified ursolic
acid, curcumin and resveratrol as top-hits. These compounds were then administered via the diet to a
mouse allograft model of prostate cancer. Combinations of the compounds greatly improved outcome, in
vivo. This outcome was, at least in part due to the modulation of glutamine metabolism, as determined via
untargeted metabolomics and metabolic flux analysis, induced by compound combinations. Moreover, the
combinations affected levels of ASCT2 and activation of STAT3, mTORC1 and AMPK. Overall, the high
throughput approach is effective for identifying combinations of natural compounds that can synergistically
contribute to chemoprevention and therapeutic outcome.