Small Molecules in the Treatment of Squamous Cell Carcinomas: Focus on Indirubins

Abstract

Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out as standard therapy. To treat advanced and metastatic cancers, targeted therapies with small molecule inhibitors are gaining increasing attention. Small molecules are a heterogeneous group of protein regulators, which are produced by chemical synthesis or fermentation. The majority of them belong to the group of receptor tyrosine kinase inhibitors (RTKIs), which specifically bind to certain RTKs and directly influence the respective signaling pathway. Knowledge of characteristic molecular alterations in certain cancer entities, such as SCC, can help identify tumor-specific substances for targeted therapies. Most frequently, altered genes in SCC include TP53, NOTCH, EGFR, and CCND1. For example, the gene CCND1, which codes for cyclin D1 protein, is upregulated in nearly half of SCC cases and promotes proliferation of affected cells. A treatment with the small molecule 5′-nitroindirubin-monoxime (INO) leads to inhibition of cyclin D1 and thus inhibition of proliferation. As a component of Danggui Longhui Wan, a traditional Chinese medicine, indirubins are used to treat chronic diseases and have been shown to inhibit inflammatory reactions. Indirubins are pharmacologically relevant small molecules with proapoptotic and antiproliferative activity. In this review, we discuss the current literature on indirubin-based small molecules in cancer treatment. A special focus is on the molecular biology of squamous cell carcinomas, their alterations, and how these are rendered susceptible to indirubin-based small molecule inhibitors. The potential molecular mechanisms of the efficacy of indirubins in killing SCC cells will be discussed as well.

Patient-Derived Human Basal and Cutaneous Squamous Cell Carcinoma Tissues Display Apoptosis and Immunomodulation following Gas Plasma Exposure with a Certified Argon Jet

“…Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are highly prevalent skin cancers [ 1 , 2 ]. SCC is a relatively slow-growing skin cancer that can expand to the surrounding tissue and further into the body (metastasis).…”

Crucial Role of Reactive Oxygen Species (ROS) for the Proapoptotic Effects of Indirubin Derivatives in Cutaneous SCC Cells

“…The natural compound indirubin was identified as an active component of the traditional Chinese medicine Danggui Longhui Wan, used for treatment of chronic and inflammatory diseases [39]. The antitumor activity of indirubin was considered, and clinical trials proved its activity in chronic myeloid leukemia and chronic granulocytic leukemia as well as in head and neck cancer.…”

“…The mode of action of indirubins in cancer cells still largely remains in the dark. Inhibition of protein kinases such as JAK, Src, GSK-3β (glycogen synthase kinase), aurora kinase A and cyclin-dependent kinases (CDKs) have been reported [39,48]. Three major types of cell death were distinguished, namely apoptosis, autophagy and necrosis.…”

Molecular Insights into Tumor Targeted Therapy by Carrier-Free Lycorine Nanoparticles in Vitro and in Vivo

“…Natural products play a very important role in the prevention and treatment of diseases [22,23]. Ly, an active natural product, has been reported to have a wide range of anti-tumor activities [24,25].…”