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J Cancer Metastasis Treat 2019;5:31 I http://dx.doi.org/10.20517/2394-4722.2019.21 Page 28 of 36

35. Resveratrol and Halofuginone Counteract TGF-b-Induced activation and proliferation of
stromal fibroblasts by Up-regulating Autophagy

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Eleonora Secomandi , Sami Ibazizen , Gwenael Rolin , Ciro Isidoro 1
1 Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del
Piemonte Orientale, Novara 28100, Italy.
2 Inserm UMR 1098, Engineering and Cutaneous Biology Team, BesanÇon 25020, France.

Cancer can be viewed as a wound that never heals. In this respect, keloids can be considered as the “benign”
counterparts of cutaneous tumors. Keloids are pathological scars derived from an altered skin wound
healing process and are characterized by hyper-activation and abnormal proliferation of stromal fibroblasts.
Among the several pro-inflammatory cytokines involved in the pathogenesis of keloids, transforming
growth factor-b (TGF-b) plays a crucial role in myofibroblast proliferation and differentiation. Resveratrol
(RV), a naturally polyphenolic compound, is a strong autophagy inducer and inhibits oxidation,
inflammation and collagen I deposition. Halofuginone (HF) is a synthetic halogenated derivate of
febrifugine, well known for its anti-fibrotic therapeutic potential.

In the present work, we focused our attention on the role of autophagy in keloid formation and
progression. We found that RV and HF counteract TGF-b-induced migration of keloid fibroblasts and,
in parallel, an increase of autophagic flux is detected, suggesting autophagy as a putative mechanism
responsible for slowing down cell motility. Moreover, HF reduces the number of Ki67+ cells, decreasing the
proliferative capacity of keloid fibroblasts. Both RV and HF attenuate α-SMA and COL1 synthesis and limit
the contraction capability of myofibroblasts within the collagen matrix, even in co-treatment with TGF-b.

36. The possible mechanism of the antioxidants on the antitumor effect of bortezomib in
melanoma and myeloma cell lines

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Angéla Takács , Eszter Lajkó , Ildikó Istenes , László Kőhidai , Orsolya Láng 1
1 Department of Genetics Cell- and Immunobiology, Semmelweis University, Budapest 1085, Hungary.
2 Department of Internal Medicine, Semmelweis University, Budapest 1085, Hungary.

Bortezomib is a proteasome inhibitor chemotherapeutic agent used to treat multiple myeloma; recently
studies offer it as a promising drug to treat melanoma. Bortezomib-induced peripheral neuropathy (BIPN)
is a dose-limiting side-effect, that can be treated with antioxidants, e.g., alpha-lipoic acid and thiamine.

The objective of our experiments was: to verify the cytotoxicity of bortezomib; to test and compare the
influence of the antioxidants on the antitumor effect of bortezomib in melanoma and myeloma.

The cells were U266 myeloma, WM35 primary and A2058 metastatic melanoma. The concentrations were:
(1) bortezomib: 20, 100 and 300 ng/mL; (2) alpha-lipoic acid: 10 and 100 µg/mL (3) thiamine: 150 and
300 nmol/L. Impedimetry (xCELLigence SP) was used to evaluate the cytotoxicity. To study the cell cycle
profile, Cell-ClockTM, a redox dye was applied and evaluated by ImageJ. Apoptosis was analyzed by flow
cytometry after annexinV assay and phospho-p53 immunostaining.

Bortezomib was cytotoxic and blocked U266 cells in the G1 phase. Alpha-lipoic acid enhanced the
cytotoxicity of bortezomib (20 ng/mL) in U266 cells, but counteracted bortezomib in melanoma cells.