Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions

Abstract

The flavonoid silymarin extracted from the seeds of Sylibum marianum is a mixture of 6 flavolignan isomers. The 3 more important isomers are silybin (or silibinin), silydianin, and silychristin. Silybin is functionally the most active of these compounds. This group of flavonoids has been extensively studied and they have been used as hepato-protective substances for the mushroom Amanita phalloides intoxication and mainly chronic liver diseases such as alcoholic cirrhosis and nonalcoholic fatty liver. Hepatitis C progression is not, or slightly, modified by silymarin. Recently, it has also been proposed for SARS COVID-19 infection therapy. The biochemical and molecular mechanisms of action of these substances in cancer are subjects of ongoing research. Paradoxically, many of its identified actions such as antioxidant, promoter of ribosomal synthesis, and mitochondrial membrane stabilization, may seem protumoral at first sight, however, silymarin compounds have clear anticancer effects. Some of them are: decreasing migration through multiple targeting, decreasing hypoxia inducible factor-1α expression, inducing apoptosis in some malignant cells, and inhibiting promitotic signaling among others. Interestingly, the antitumoral activity of silymarin compounds is limited to malignant cells while the nonmalignant cells seem not to be affected. Furthermore, there is a long history of silymarin use in human diseases without toxicity after prolonged administration. The ample distribution and easy accessibility to milk thistle-the source of silymarin compounds, its over the counter availability, the fact that it is a weed, some controversial issues regarding bioavailability, and being a nutraceutical rather than a drug, has somehow led medical professionals to view its anticancer effects with skepticism. This is a fundamental reason why it never achieved bedside status in cancer treatment. However, in spite of all the antitumoral effects, silymarin actually has dual effects and in some cases such as pancreatic cancer it can promote stemness. This review deals with recent investigations to elucidate the molecular actions of this flavonoid in cancer, and to consider the possibility of repurposing it. Particular attention is dedicated to silymarin's dual role in cancer and to some controversies of its real effectiveness.

Keywords: antioxidant; cancer; invasion; migration; milk thistle; silybin; silymarin.

Figure 1.

A glimpse of the multiple brands and presentations of silymarin compounds in the US and European markets with the resultant “vulgarization.” There are many “silymarins” developed in well accredited pharmaceutical laboratories, but there are also many produced by scarcely known sources. Most can be acquired through the Internet.

Figure 2.

Milk thistle and the chemical structure of silybin (C25 H22 O10), with its proprietary numbering. Of note, is the similarity between silybin and steroid hormones. The lower panel shows silibinin's structural formula where 3 different chemical groups can be identified: a taxifolin and a coniferyl alcohol united by an oxirane ring. According to Biedermann et al, “the 20-OH group was established to be the most active radical scavenging moiety and also the most important group responsible for the lipoperoxidation inhibitory activity.” Positions 2-3 also play a role in antioxidant activity because these positions can be oxidized to produce 2-3 dehydrosilybin (see Figure 3). Silybin has 5 hydroxyl groups in positions 3, 5, 7, 20, and 23 which are the targets to produce silybin derivatives. Positions 7 and 20 are usual sites of glucuronidation of silybin during its conjugation in human metabolism.

Figure 3.

2-3 dehydrosilybin has 25-fold more antioxidant activity than silybin. Taxifolin and quercetin have more antioxidant activity than 2-3 dehydrosilybin. Small amounts of 2-3 dehydrosilybin are found in silymarin.

Figure 4.

Nomenclature diagram of the different components of milk thistle seed and silymarin. Isosilybin B seems to be the most powerful anticancer fraction. Silymarin and Silibinin are different concepts, however some older publications use both terms interchangeably. Silibinin is the more active form of the silymarin extract. Only silymarin extracts are available in pharmacies while researchers usually use silibinin for their experiments. Standard silymarin extracts usually contain 33.5% silybin, 13% silychristin, 8.35% isosilybin, 3.5% silydianin (see Figure 5).

Figure 5.

Similarities and differences among silymarin's components.

Figure 6.

Silymarin impedes clathrin-dependent endocytosis. In receptor-mediated endocytosis, or clathrin-mediated endocytosis, cells incorporate hormones, proteins, and sometimes viruses in a selective manner that depends on a ligand-receptor interaction. (1) The ligand receptor interaction takes place on the cell surface. (2) An adapter protein and clathrin “coat” the internal surface of the receptors and a process of membrane invagination starts. (3) Advanced invagination process. (4) The adaptor protein and clathrin are released. Silymarin impedes this mechanism of endocytosis. Clathrin-dependent endocytosis of surface receptors participates in cellular signaling pathways. Clathrin seems to be a valid target in cancer therapy.

Figure 7.

Methods to increase silymarin's bioavailability.

Figure 8.

Different effects of silymarin according to context.