Sanguinarine induces apoptosis and inhibits growth of cancer cells

May 21, 2013, Featured in Cancer and Natural Medicines, 0 Comments

Bloodroot (Sanguinaria canadensis) has been used historically by some Native American tribes as a medicinal agent to stimulate the digestive system. It has also been used medicinally as a remedy for fevers, as an expectorant for chronic bronchitis and as a local application in chronic eczema, especially when secondary to varicose ulcers.

Bloodroot is generally prescribed as an external treatment as it is poisonous if ingested in large amounts. In toxic doses, it causes burning in the stomach, intense thirst, vomiting, faintness vertigo, intense prostration with dimness of eyesight. Bloodroot grows primarily in North America and in India. Sanguinarine, the major active compound found in bloodroot, is a very impressive natural medicine. Sanguinarine is a benzophenanthrene alkaloid. It has also been used as an antimicrobial.

More recently, sanguinarine has been used in toothpaste and mouthwash to prevent gingivitis and other inflammatory conditions of the mouth. It has peculiar ability to kill both gram negative and positive bacteria. In addition, mouthwashes containing sanguinarine are known to be able to control oral fungal infections, such as candida. Other than its anti-inflammatory effects, sanguinarine is currently well known for its anti-cancer effects. Large numbers of studies have demonstrated sanguinarine is able to induce apoptosis, therefore inhibit the growth of tumours.

In cancer, the natural processes that lead to apoptosis are often blocked, preventing the removal of cancer cells and thus facilitating the growth of tumor tissue. Survivin is a member of a group of proteins called IAPs (inhibitor of apoptosis proteins). The inhibition of these IAP proteins is critical for the induction of apoptosis. Survivin is highly expressed in most cancers (lung, colon, breast, prostate, pancreas, high-grade lymphomas, neuroblastomas, gastric) and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival.

Survivin has been shown to increase tumor resistance to various apoptotic stimuli, primarily through caspase-dependent mechanisms, although it can also block apoptosis in a caspase-independent fashion. Caspases are a family of enzymes known as cysteine aspartyl proteases that play a central role in process of apoptosis. Activation of these enzymes leads to fragmentation of DNA and ultimately the death and clearance of cancer cells.

Conversely, antagonizing survivin in tumor cells induces apoptosis. Thus, antisurvivin therapy is an attractive cancer treatment strategy. Sanguinarine inhibits survivin. Data showed that the effect of sanguinarine on survivin was not only at the transcriptional level; rather there was degradation of survivin protein. This occurred via a proteasome-dependent pathway; specifically sanguinarine enhanced survivin degradation via the ubiquitin-proteasome system.

Protein degradation through the ubiquitin-proteasome system is a major component in cellular metabolism and regulates numerous cell functions. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. 

The universal character of the tumor-associated antigen survivin. 

Survivin, a cancer target with an emerging role in normal adult tissues.

Recent advances in anti-survivin treatments for cancer.

Critical Role of a Survivin/TGF-β/mTORC1 Axis in IGF-I-Mediated Growth of Prostate Epithelial Cells.

Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.

STAT3 (signal transducer and activator of transcription 3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a critical therapeutic target. Tumor cells depend on STAT3 for continued rapid growth and avoidance of apoptosis. STAT3 is constitutively activated in a wide variety of tumours, including colorectal cancer, liver cancer, breast cancer, prostate cancer, multiple myeloma, and glioblastoma. Perhaps half or more of human tumors contain persistently active STAT3. Survivin is activated at the genetic level by STAT3. Thus, direct inhibition of STAT3 signaling can block the expression of survivin protein and induce apoptosis. 

Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.

Furthermore, STAT3 pathway controls cancer stem cell survival. Studies show that the development and maintenance of cancer stem cells are dependent on STAT3 signaling. Tumor-initiating or cancer stem cells are known to have unlimited self-reproductive ability and resistance to anti-cancer drugs.

STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells.

STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy?

STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH⁺/CD133⁺ stem cell-like human colon cancer cells.

Sanguinarine inhibits STAT3 activation, a known promotor of survivin gene activity. Thus, sanguinarine, properly administered, can effectively block both survivin and STAT3 pathways. Sanguinarine also overcomes p-glycoprotein mediated multidrug resistance (MDR). P-glycoprotein is an efflux pump of the MDR genes subfamily. MDR of tumor cells is the main cause of the failure of chemotherapy.

Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion.

Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells.

In addition, Sanguinarine causes the production of large amounts of reactive oxygen species (ROS), in particular hydrogen peroxide, which may deplete cellular antioxidants and provide a signal for rapid execution of apoptosis. Beyond ROS involvement in carcinogenesis, increased ROS level can inhibit tumor cell growth. Indeed, in tumors in advanced stages, a further increase of oxidative stress, such as that occurs when using several anticancer drugs and radiation therapy, can overcome the antioxidant defenses of cancer cells and drive them to apoptosis.

Glutathione, the primary anti-oxidant in the cell, can be synthesized in the body. Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negative feedback inhibition of its own synthesis. If glutathione levels decline beyond a certain point, cancer cells will die of oxidative stress. Sanguinarine actually interacts directly with the glutathione molecule, thereby depleting it in the cells.

Research has also clearly demonstrated that in prostate cancer cells, continuous treatment with 5 microM sanguinarine induced an early (within 10 min) cellular reduced glutathione depletion, followed by a caspase 3/7-dependent apoptotic response within 2 hr. In 5 microM concentrations, sanguinarine is a powerful inducer of apoptosis. In fact, this research shows antioxidants such as dithiothreitol (DTT) or N-acetylcysteine (NAC) treatment can not prevent this decrease in glutathione. But, antioxidants such as NAC are involved in glutathione regeneration. Thus, pretreatment with the thiol antioxidants NAC and glutathione may abrogate the killing activity of sanguinarine.

Production of hydrogen peroxide and redox cycling can explain how sanguinarine and chelerythrine induce rapid apoptosis. 

Sanguinarine-induced apoptosis: generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL.

Rapid human melanoma cell death induced by sanguinarine through oxidative stress.

Sanguinarine-induced apoptosis is associated with an early and severe cellular glutathione depletion.

Sanguinarine, a benzophenanthridine alkaloid, induces apoptosis in MDA-MB-231 human breast carcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. 

Sanguinarine also induces apoptosis in primary effusion lymphoma (PEL) cells and pancreatic cancer cells via different mechanisms. Both PEL and pancreatic cancer are known as incurable, aggressive, and develop rapid resistance to conventional chemotherapy. 

Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells. 

Sanguinarine induces apoptosis of human pancreatic carcinoma AsPC-1 and BxPC-3 cells via modulations in Bcl-2 family proteins. 

Sanguinarine was added to Prostazym formula, because it can powerfully kill cancer cells by inhibition of Stat3/Survivin signaling pathway and depleting cellular glutathione. Prostazym kills cancer cells only and does not harm your healthy cells. But, it should be avoided during pregnancy. In addition, it has also been proven that gastric problems could be induced when bloodroot is given with herbs that cause gastric irritation, such as ginger and coffee.

Comments are closed.