Shikonin Derivatives from Onsoma visianii Decrease Expression of Phosphorylated STAT3 in Leukemia Cells and Exert...

Area of Science:

• Pharmacology
• Oncology
• Molecular Biology

Background:

• Chronic lymphocytic leukemia (CLL) and B-cell prolymphocytic leukemia (B-PLL) are B-cell malignancies with limited treatment options.
• Shikonins, natural compounds from *Onosma visianii*, have shown potential antitumor activity, but their effects on CLL and B-PLL are largely unknown.

Purpose of the Study:

• To investigate the antitumor effects of shikonin derivatives on mouse CLL (BCL1) and human B-PLL (JVM-13) cells.
• To elucidate the molecular mechanisms underlying the cytotoxic and anti-proliferative activities of shikonin derivatives.

Main Methods:

• Cytotoxicity was assessed using MTT assays.
• Cell death, proliferation, cell cycle, and molecular marker expression were analyzed by flow cytometry.
• STAT3-regulated gene expression was quantified using quantitative real-time PCR (q-RT-PCR).
• In vivo antitumor activity was evaluated in mice bearing BCL1 leukemia.

Main Results:

• Isobutyrylshikonin (IBS) and α-methylbutyrylshikonin (MBS) demonstrated significant antitumor activity in vitro and in vivo.
• These derivatives induced cell cycle arrest and apoptosis, inhibited proliferation, and reduced leukemia cell burden in mice.
• IBS and MBS decreased the phosphorylation of STAT3 and its downstream targets.
• The addition of AG490 (a Jak2 inhibitor) enhanced cell death, confirming the role of STAT3 inhibition.

Conclusions:

• Shikonin derivatives, particularly IBS and MBS, possess potent antitumor properties against CLL and B-PLL.
• The mechanism involves the inhibition of STAT3 phosphorylation, leading to apoptosis induction, proliferation inhibition, and attenuation of leukemia stemness.
• These findings suggest shikonins as potential therapeutic agents for B-cell leukemias.