Triptolide: A new star for treating human malignancies
Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia
Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb
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
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
Updated with more research links and a source for piperlongumine! This natural compound is apparently effective against so many different cancer types. I’ve only included links to the free research articles, but there are many more behind the paywalls!
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
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
Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells
New Mild and Simple Approach to Isothiocyanates: A Class of Potent Anticancer Agents
“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”.
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.
Video originally posted by Genentech. From their site:
“Apoptosis is often evaded in cancer cells via overexpression of anti-apoptotic Bcl-2 family proteins and dysregulation of pro-apoptotic proteins. The Bcl-2 family members bind pro-apoptotic proteins to prevent apoptosis mediated by the intrinsic apoptotic pathway.
Bcl-2 is overexpressed in several hematologic malignancies, including non-Hodgkin’s lymphoma. Preclinical studies demonstrate that Bcl-2 acts as a key regulator of the intrinsic apoptotic signaling pathway by sequestering and neutralizing pro-apoptotic molecules, such as Bax.7 Thus, the anti-apoptotic protein promotes B-cell survival by inhibiting apoptosis, which may result in oncogenic chemotherapy resistance in hematologic malignancies”.
This cool image is also Genentech’s.
Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia
A new face of BCL-2 inhibition in CLL – inhibiting BCL-2 can promote cell death by perturbing calcium signaling!
“Zhong et al focus on a different facet of BCL-2, the BH4 domain that is involved in the interaction with IP3R. Using an oligopeptide derived from a site on IP3R found to be involved in binding BCL-2, the authors had previously demonstrated the ability to disrupt the BCL-2:IP3R complex and alter calcium signaling. This current report is noteworthy in two ways: first, it reports a modification of the peptide that increased cytoplasmic calcium concentrations; and second, it finds that CLL cells are selectively susceptible to death induced by the calcium signaling…”
“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
“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:
Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions
Natural Compounds as Regulators of the Cancer Cell Metabolism
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?
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 cross hairs
“Inhibition of mitochondrial pyruvate dehydrogenase kinase (PDK) by dichloroacetate may be exploited to reverse the abnormal metabolism of cancer cells from glycolysis to glucose oxidation. As PDK negatively regulates pyruvate dehydrogenase, dichloroacetate indirectly stimulates the pyruvate to acetyl-CoA conversion. Dichloroacetate has been shown to downregulate the aberrantly high mitochondrial membrane potential of cancer cells, increase mitochondrial ROS generation and activate K+ channels in malignant, but not in normal cells143. Dichloroacetate also upregulated the expression of the K+ channel Kv1.5, which is often underexpressed by tumour cells, through the transcription factor nuclear factor of activated T cells (NFAT1). Dichloroacetatenormalized mitochondrial functions were accompanied by reduced proliferation, increased apoptosis and suppressed tumour growth without apparent toxicity, suggesting that the mitochondria–NFAT–Kv axis and PDK represent promising anticancer drug targets”.
Targeting mitochondria for cancer therapy
Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC
Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage
Time for another natural anti-cancer compound that works in a manner similar to gossypol; it up-regulates the pro-apoptotic BH3 protein Noxa. It comes from St. John’s Wort.
“We previously reported that hyperforin, a phloroglucinol purified from Hypericum perforatum, induces the mitochondrial pathway of caspase-dependent apoptosis in chronic lymphocytic leukemia (CLL) cells ex vivo, and that this effect is associated with upregulation of Noxa, a BH3-only protein of the Bcl-2 family. Here, we investigated the role of this upregulation in the pro-apoptotic activity of hyperforin in the cells of CLL patients and MEC-1 cell line. We found that the increase in Noxa expression is a time- and concentration-dependent effect of hyperforin occurring without change in Noxa mRNA levels. A post-translational regulation is suggested by the capacity of hyperforin to inhibit proteasome activity in CLL cells. Noxa silencing by siRNA reduces partially hyperforin-elicited apoptosis. Furthermore, treatment with hyperforin, which has no effect on the expression of the prosurvival protein Mcl-1, induces the interaction of Noxa with Mcl-1 and the dissociation of Mcl-1/Bak complex, revealing that upregulated Noxa displaces the proapoptotic protein Bak from Mcl-1. This effect is accompanied with Bak activation, known to allow the release of apoptogenic factors from mitochondria. Our data indicate that Noxa upregulation is one of the mechanisms by which hyperforin triggers CLL cell apoptosis. They also favor that new agents capable of mimicking specifically the BH3-only protein Noxa should be developed for apoptosis-based therapeutic strategy in CLL”.
Hyperforin structure
Differential Cell Death: The Ultimate Approach to Defeating Cancer 