Shikonin reduces the tumour formation and IL-17 in a model of colorectal cancer associated to chronic colitis in C57BL/6 mice

 

Shikonin has been studied as anti-inflammatory [1] and anticancer agent [2]. We previously described the cytotoxic dose-dependent effect on Caco-2 cells of shikonin through the induction of apoptosis by an increase in caspase-3 and the inhibition of the regulating protein Bcl2 [3]. It is known that chronic intestinal inflammation is one of the factors that can trigger a cancerous process. Now, we present the results obtained in a similar experimental method of colorectal cancer (CRC) associated to ulcerative colitis (UC) in C57BL/6 mice. We also evaluated the effect of shikonin on the modulation of IL-17 response.

Shikonin was administered to the mice at 5 mg/kg p.o. (24 doses). AOM (7.5 mg/kg, i.p., was given 7 days before the first cycle of DSS (2.5%). Two additional cycles of DSS at 2% were done. Each cycle consisted in 7 days of DSS followed by 14 days of relapse. Mice were sacrificed at day 63 by cervical dislocation and their colons were removed. 5-Aminosalicylic acid (5-ASA, 75 mg/kg) was used as positive control.

Mice treated with AOM/DSS (negative control) suffer an inflammatory process in colon with loss of epithelial architecture and appearance of neoplastic polyps. Shikonin treatment reduced colon shortening induced by AOM/DSS, and decreased the severity of inflammation (60%) according to the disease activity index determined at the end of every DSS cycle and the day of sacrifice. Although shikonin did not prevent the appearance of tumors, it reduced the number (40%) and the size of them. The level of IL-17 decreased by 64%. Th17 cell response through cytokine release produced an inflammatory response of tissue and stimulated the appearance and progression of tumors in this experimental model of CRC.

Taken together these findings and the previous results, shikonin can be considered as a promising therapeutic agent for the adjuvant therapy for colorectal cancer by reducing the number and size of tumors.

References:

[1] Andújar I, Ríos JL, Giner RM, Recio MC. Pharmacological properties of shikonin – a review of literature since 2002. Planta Med 2013; 79: 1685 – 1697

[2] Andújar I, Recio MC, Giner RM, Ríos JL. Traditional Chinese medicine remedy to jury: the pharmacological basis for the use of shikonin as an anticancer therapy. Curr Med Chem 2013; 20: 2892 – 2898

[3] Ríos JL, Andújar I, Martí A, Giner RM, Cerdá JM, Recio MC. Shikonin induces apoptosis in Caco-2 cells by an increase in caspase-3 and the inhibition of the regulating protein Bcl2. Planta Med 2015; 81: PM186