Atorvastatin blocks Sonic Hedgehog medulloblastoma progression through apoptosis

R.E. Gordona,b*, Z.I. Abramovaa**

aKazan Federal University, Kazan, 420008 Russia

bFox Chase Cancer Center, Philadelphia, 19111 USA

E-mail: *renata.e.gordon@gmail.com, **ziabramova@mail.ru

Received July 25, 2017

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Abstract

Aberrant activation of Sonic Hedgehog signaling transduction leads to formation of numerous   malignancies, including medulloblastoma (MB) – the most common malignant pediatric tumor. Earlier, we have shown that endogenous cholesterol acts as a direct activator of the Sonic Hedgehog signaling and is a promising target for treating MB. Histochemical analysis of the effect of atorvastatin, which is widely used in clinical practice as a cholesterol biosynthesis inhibitor, revealed a high level of cell death in the tumor tissue via apoptosis. These data show the potential of using statins for the targeted therapy of medulloblastoma, as well as other Sonic Hedgehog-driven malignancies.

Keywords: medulloblastoma, Sonic Hedgehog, statins, atorvastatin, cholesterol, apoptosis

Acknowledgments. The study was supported by the Russian Government Program of Competitive Growth of Kazan Federal University.

Figure Captions

Fig. 1. The scheme of Shh signal transduction in the cell.

Fig. 2. The primary cell culture of mouse MB cells after 72-h incubation: a – control sample (DMSO), b – atorvastatin (10 nmol), c – atorvastatin (50 nmol). (dose-dependent decrease in the number of viable cells, identified by the low number of cells per visual field). Scale: 10 ?m.

Fig. 3. The assessment of the proliferation level (BrdU-positive cells) in the primary mouse MB cell culture after 72-h incubation using IF-analysis: a – control sample (DMSO), b – atorvastatin (10 nmol), c – atorvastatin (50 nmol). Scale: 10 ?m.

Fig. 4. The quantitative analysis of proliferation (BrdU-positive cells, %) in the primary mouse MB cell culture after 72-h incubation. * – p < 0.05, ** – p < 0.005.

Fig. 5. The analysis of Gli1 protein expression in the primary culture of Ptch1+/– MB cell culture by Western blotting. GAPDH protein analysis was used as a control variant.

Fig. 6. The IF-analysis of apoptosis level (caspase3-positive cells) in the tissue of Ptch1+/– MB mice after three weeks of atorvastatin administration: a – control sample (DMSO), b – atorvastatin (10 mg/kg/day), c – atorvastatin (40 mg/kg/day). Scale: 10 ?m.

Fig. 7. The quantitative analysis of apoptosis level (caspase3-positive cells, %) in mouse MB allograft tissues after three weeks of treatment with atorvastatin. * – p < 0.05, ns – p > 0.05.

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For citation: Gordon R.E., Abramova Z.I. Atorvastatin blocks Sonic Hedgehog medulloblastoma progression through apoptosis. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2017, vol. 159, no. 4, pp. 550–563. (In Russian)


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