Sulforaphane, the Phytochemical that could (kill cancer stem cells that is)!

broccoli-chemistry

Sulforaphane is an anti-cancer compound in cruciferous vegetables, mostly commonly credited to Broccoli. Here’s another another amazing natural compound in the Isothiocyanate family. It down regulates glutathione, increases ROS, and inhibits WNT signaling in the cancer cells. As usual, follow the links for the research.

Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells

Phytochemicals as Innovative Therapeutic Tools against Cancer Stem Cells

Implications of Cancer Stem Cell Theory for Cancer Chemoprevention by Natural Dietary Compounds

Sulforaphane Retards the Growth of Human PC-3 Xenografts and Inhibits HDAC Activity in Human Subjects

Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics

 

Noscapine: from cough syrup to cancer

Noscapine_3d_animotrivin_noscapine_hcl_2

Noscapine is a phthalide isoquinoline non-narcotic alkaloid derived from the opium poppy Papaver somniferum, with mild analgesic, antitussive, and potential antineoplastic activities. Noscapine exerts its antitussive effects through the activation of sigma opioid receptors. This agent appears to exert its antimitotic effect by binding to tubulin, resulting in a disruption of microtubule assembly dynamics and subsequently, the inhibition of mitosis and tumor cell death.

Here’s another mild compound that has been in use for quite some time and could be re-purposed as a cancer fighting drug, particularly in a cocktail approach. Its anti-mitotic properties would come in quite handy. As usual follow the links to find out what this compound offers.

A Safe Cough Suppressant with Newly Discovered Effects in Treating Cancer and Stroke

Microtubules, leukemia, and cough syrup

Study Shows That A Cough Medicine Ingredient Could Effectively Treat Prostate Cancer

Noscapine and Its Analogues as Anti-Cancer Agents

Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

Noscapine, a benzylisoquinoline alkaloid, sensitizes leukemic cells to chemotherapeutic agents and cytokines by modulating the NF-κB signaling pathway

Noscapine Induced Apoptosis via Downregulation of Survivin in Human Neuroblastoma Cells Having Wild Type or Null p53

Piperlongumine: a natural plant-based compound that is selectively cytotoxic to cancer cells

 

Piper_longum D440820

Scientists at the Broad Institute and Massachusetts General Hospital (MGH) have discovered a novel compound that blocks this response to oxidative stress selectively in cancer cells but spares normal cells, with an effectiveness that surpassed a chemotherapy drug currently used to treat breast cancer. Their findings, based on experiments in cell culture and in mice, appear online in Nature on July 13.

The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don’t need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.

Taking out a cancer’s co-dependency:
Novel compound selectively kills cancer cells by blocking their response to oxidative stress

Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (Review)

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Selective killing of cancer cells by a small molecule targeting the stress response to ROS

Piperlongumine Induces Apoptosis and Synergizes with Cisplatin or Paclitaxel in Human Ovarian Cancer Cells

Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer

Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells

Auranofin (aka Ridaura) : An FDA approved anti-rheumatic drug that induces oxidative stress and apoptosis in CLL cells

Auranofin-3D-vdW

“By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL”.

Auranofin Induces Lethal Oxidative and Endoplasmic Reticulum Stress and Exerts Potent Preclinical Activity against Chronic Lymphocytic Leukemia

Auranofin Induces a Reversible In-Vivo Stress Response That Correlates With a Transient Clinical Effect In Patients With Chronic Lymphocytic Leukemia

Effect of auranofin on oxidative and endoplasmic reticulum stress as well as anti-CLL activity with proteasome inhibitor

Targeting the Redox System to Overcome Mechanisms of Drug Resistance in Chronic Lymphocytic Leukemia

Phase I and II Study of Auranofin in Chronic Lymphocytic Leukemia (CLL)

New NIH Center Broadens Scope of Translational Research

Nearly 30 years after auranofin gained approval from the U.S. Food and Drug Administration to treat rheumatoid arthritis, researchers are repurposing the drug for a possible new use: chronic lymphocytic leukemia (CLL). Moreover, the arthritis drug could emerge as a model for accelerating patients’ access to other repurposed drugs or for rescuing drugs that the pharmaceutical industry has abandoned and now are languishing on companies’ shelves, researchers say.

“What we did was go from in vitro experiments directly into patients,” said Scott Weir, Pharm.D., Ph.D., director of the Institute for Advancing Medical Innovation at the University of Kansas Medical Center, one of several test sites nationwide, which soon will include the National Heart, Lung, and Blood Institute.

“We didn’t feel we needed to go through the traditional drug paradigm,” he said, given auranofin’s earlier testing for safety and efficacy.

As a result, less than 2 years after scientists discovered that auranofin could kill CLL cells in the lab, researchers began dosing the first relapsed CLL patient in a clinical trial. That compares with, on average, 8–10 years to reach a similar stage in drug development for a new drug, according to Weir, one of several authors of a recent commentary in Cancer Research about the pilot project.

The repurposing of older drugs such as auranofin, as well as second looks at unapproved agents stuck in the regulatory pipeline, is part of an intense systematic approach to translational research embodied in the first new center at the National Institutes of Health in more than a decade. The National Center for Advancing Translational Sciences (NCATS), which replaced the National Center for Research Resources earlier this year, incorporates many of the former center’s programs.

Shikonin – another natural mitocan

“Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca2+ and ROS levels. This deregulation led to a breakdown of the mitochondrial membrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy”.

Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

Shikonin circumvents cancer drug resistance by induction of a necroptotic death

shikonin

Metabolic Targets in the Crosshairs

“Mitochondria are emerging as idealized targets for anti-cancer drugs. One reason for this is that although these organelles are inherent to all cells, drugs are being developed that selectively target the mitochondria of malignant cells without adversely affecting those of normal cells. Such anticancer drugs destabilize cancer cell mitochondria and these compounds are referred to as mitocans, classified into several groups according to their mode of action and the location or nature of their specific drug targets. Many mitocans selectively interfere with the bioenergetic functions of cancer cell mitochondria, causing major disruptions often associated with ensuing overloads in ROS production leading to the induction of the intrinsic apoptotic pathway. This in-depth review describes the bases for the bioenergetic differences found between normal and cancer cell mitochondria, focusing on those essential changes occurring during malignancy that clinically may provide the most effective targets for mitocan development. A common theme emerging is that mitochondrially mediated ROS activation as a trigger for apoptosis offers a powerful basis for cancer therapy. Continued research in this area is likely to identify increasing numbers of novel agents that should prove highly effective against a variety of cancers with preferential toxicity towards malignant tissue, circumventing tumor resistance to the other more established therapeutic anti-cancer approaches”. Follow the links:

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Choosing between glycolysis and oxidative phosphorylation: A tumor’s dilemma?

Targeting Cell Metabolism In Chronic Lymphocytic Leukaemia (CLL); A Viable Therapeutic Approach?

Stalling the Engine of Resistance: Targeting Cancer Metabolism to Overcome Therapeutic Resistance

Is Cancer a Metabolic Disease?

Cancer as a Metabolic Disease

Targeting mitochondria for cancer therapy

Mitochondrial permeability transition pore as a selective target for anti-cancer therapy

Mitochondrial uncoupling and the reprograming of intermediary metabolism in leukemia cells

Mitocans as Novel Agents for Anticancer Therapy: An Overview

Apoptosis: from biology to therapeutic targeting

 

Metabolic targets in the crosshairs

Metabolic targets in the cross hairs