Biotech World: October 2017

Tuesday, October 31, 2017

Herbal supplements and cancer

Herbal supplements as well as dietary supplements could cause cancer. According to recent research one in five cases of chemical-induced liver damage come from herbal and dietary supplements. Herbal remedies containing aristolochic acids (AA), a compound found in leafy, flowery vines called Aristolochia (or birthwort) and Asarum is the most potent carcinogen that have been linked to several types of cancer. Aristolochic Acid is a natural product of plants used in some weight loss supplements too. A study, published in Science Translational Medicine found that in 78 percent of liver cancer samples collected in Taiwan showed a distinctive mutation consistent with AA exposure. The research team looked at 98 samples of hepatocellular carcinoma, the most common type of liver cancer, and the most common cause of death in people with cirrhosis [1]. Also cancers of the upper urinary tract (renal pelvis and ureter) and bladder have been reported among individuals who had kidney damage caused by the consumption of herbal products containing AA.

Aristolochic acid is absorbed from the gastrointestinal tract and distributed unchanged and/or in metabolized form throughout the body. The major activation pathway of AA involves reduction of the nitrogroup, and is catalysed by several human cytosolic and microsomal enzymes such as hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase (NQO1), hepatic microsomal cytochrome P450 (CYP)1A2 and renal microsomal NADPH:CYP reductase – NQO1 being the most important [2]. During reductive activation, aristolochic acids form an electrophilic cyclic N-acylnitrenium ion that reacts with purine bases to form DNA adducts. These DNA adducts found in patients with liver, bladder and renal cancer, act as biomarker for exposure to AA.

AA has been officially banned in Europe since 2001 and in Singapore since 2004. Some herbs that contain AA have been banned in Taiwan since 2003, and in China, the use of some, but not all, AA-containing herbs in traditional medicine is restricted. But the United States Food and Drug Administration has issued strong warnings about herbs containing AA. Food and Drug Administration (FDA) is advising consumers to immediately discontinue use of any botanical products containing aristolochic acid. These products may have been sold as "traditional medicines" or as ingredients in dietary supplements [3].

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Wednesday, October 11, 2017

Neuroligin-3 and brain cancer

NLGN3 (neuroligin 3) is a mitogen/synaptic protein that promotes glioma proliferation through the PI3K–mTOR pathway. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K–mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. The tumors, called high-grade gliomas (HGG), are a group of deadly brain cancers that include adult glioblastoma, anaplastic oligodendroglioma, pediatric glioblastoma (GBM) and pediatric diffuse intrinsic pontine glioma (DIPG) [1]. Recent research in Stanford University found that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Neuroligin-3 activates multiple cancer promoting signaling pathways and increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function [2]. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors block the release of NLGN3 into the tumor microenvironment and robustly pause HGG xenograft growth [3]. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth [4]. Recent research suggests that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain.