Anti-tumor effects of shikonin derivatives on human medullary thyroid carcinoma cells

Abstract

New treatment options are needed for medullary thyroid carcinoma (MTC), a highly metastasizing neuroendocrine tumor that is resistant to standard radiotherapy and chemotherapy. We show that the following shikonin derivatives inhibit cell proliferation and cell viability of the MTC cell line TT: acetylshikonin, β,β-dimethylacrylshikonin, shikonin and a petroleum ether extract of the roots of Onosma paniculata containing several shikonin derivatives. The unsubstituted shikonin derivative was found to be the most effective compound with an IC50 of 1.1 µM. The cell viability of normal human skin fibroblasts, however, was not affected by the tested substances, indicating that shikonin derivatives might be selectively toxic for cancer cells. We further report that migration and invasion of TT cells were inhibited at non-toxic concentrations. Finally, shikonin was tested in vivo using the chick chorioallantoic membrane assay, where it significantly reduced tumor growth by inhibiting cell proliferation and inducing apoptosis. In summary, our results suggest that shikonin derivatives have the potential for the treatment of medullary thyroid carcinomas.

Synthesis of Novel Shikonin Derivatives and Pharmacological Effects of Cyclopropylacetylshikonin on Melanoma Cells

“…In previous investigations, we demonstrated that 1 also induced apoptosis caspase 3 dependently after 24 h [ 8 ]. The induction of apoptosis by shikonin derivatives was also reported in other types of cancer such as medullary thyroid carcinoma cells [ 6 ], human gastric cancer cells, and human breast cancer cells [ 38 , 39 ]. To confirm apoptosis induction, immunoblotting and flow cytometric experiments were performed.…”

“…In previous studies, roots of O. paniculata were phytochemically and pharmacologically investigated and emerged as promising research objects [ 5 , 6 , 7 , 8 ]. We were able to isolate several shikonin derivatives and investigated their effects on various tumor cell lines including leukemia, medullary thyroid carcinoma, glioblastoma, colon cancer, breast cancer, and melanoma [ 5 , 6 , 7 , 8 ]. Overall, β , β -dimethylacrylshikonin ( 1 ) was the most cytotoxic compound of all isolated derivatives.…”

Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T‐lymphokine‐activated killer cell‐originated protein kinase.

“…erythrorhizon root (Gwon et al, 2012; Pietrosiuk et al, 2006; Zhao, Wu, Wu, Zhao, & Chen, 2016), exhibits various pharmacological activities including induction of autophagy, anti‐oxidative, anti‐inflammatory, anti‐proliferative, anti‐fertility, and anticancer effects (He, Li, Su, Huang, & Zhu, 2016; Pietrosiuk et al, 2006; Skrzypczak et al, 2015; Wu et al, 2011; Zeng, Zhu, & Su, 2018). Several studies have demonstrated that the compound inhibits growth of a variety of cancers, including colorectal, breast, liver, medullary thyroid carcinoma, pancreas, melanoma, and gastric cancers (Cho & Choi, 2015; Hasenoehrl et al, 2017; Kim, Lee, Park, & Choi, 2016; Kretschmer et al, 2012; Park et al, 2017; Vukic et al, 2017; Zeng, Liu, & Zhou, 2009). Mechanistically, acetylshikonin has been reported to act by down‐regulating NF‐κB, Bcl‐2 expression, and CYP2J2 activity, and the IL‐8/MMP axis, or by up‐regulating expression of haem oxygenase‐1 (Cho et al, 2018; Cho & Choi, 2015).…”

The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

“…As a major component of Zicao, shikonin exhibits anti-tumor activity [4,19] and has been reported to be less cytotoxic [20][21][22][23] and circumvent drug resistance [24] of various tumor cell lines. In the present study, we tested the effects of shikonin on K562 cells.…”