Berberine: a natural overachiever!

Berberine Structure

There’s simply too much information for me to completely compile and post on this incredibly powerful compound! Studies indicate that it can help treat diabetes, obesity, gut health, and cancer to name just a few! It has been used in traditional chinese medicine for thousands of years and comes from goldenseal, barberry, Oregon grape, and tree tumeric. See below for just a few of the many links to primary research on this near-miraculous product. I’ve linked a source below for a liposomal formulation of it too.

Berberine (BRB), an alkaloid with anti-hyperglycemic and hypolipidemic properties, was recently shown to inhibit cellular lipogenesis, and respiratory complex I activity, exerting antiproliferative activity against tumor cell lines and tumor xenotransplants7–10, through mechanisms involving mitochondrial functions11,12. We, therefore, explored the in vitro cytotoxic and cytostatic effects of BRB on circulating leukemic cells derived ex-vivo from the peripheral blood of CLL patients and cultured in the presence of activating microenvironment stimuli.

Berberine affects mitochondrial activity and cell growth of leukemic cells from chronic lymphocytic leukemia patients

Effects of Berberine and Its Derivatives on Cancer: A Systems Pharmacology Review

Berberine, an Epiphany Against Cancer

The Anti-Cancer Mechanisms of Berberine: A Review

Source: (Of course Amazon carries tons of berberine, but liposomal form is harder to find)

Berberine 97% Liposomal

Triptolide: Chinese Medicine Strikes Again!

Triptolide is a diterpenoid epoxide which is produced by the thunder god vine, Tripterygium wilfordii. It has in vitro and in vivo activities against mouse models of polycystic kidney disease[2] and pancreatic cancer, but its physical properties[3] and severe toxicity[4] limit its therapeutic potential. Consequently, a synthetic water-soluble prodrug, minnelide, is being studied clinically instead.

Triptolide has broad applicability to multiple cancer types. I’ve enclosed several links to the primary research below. Links to Minnelide, a more water-soluble synthetic prodrug of triptolide that is converted in vivo, are included as well. Thunder God Vine is a natural source of triptolide. Be warned that toxicity is a concern so approach with caution.

Triptolide: A new star for treating human malignancies

Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia

Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1

Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells

Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb

Minnelide, a novel drug for pancreatic and liver cancer

Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer

Putting the Squeeze on Tumor Energy Production

A time-tested method to identify and disrupt criminal activity is to “follow the money” since the illicit proceeds from crime are required to underwrite it. By analogy, strategies to target cancer involve following and disrupting the flow of ATP and NADH, the energetic and redox “currencies” of the cell, respectively, since the tumor requires high levels of ATP and NADH, not only for metastasis and proliferation, but also, on a more basic level, for survival. Accordingly, four broad ATP reduction strategies to impact and potentially derail cancer energy production are highlighted herein: 1) small molecule energy-restriction mimetic agents (ERMAs) that target various aspects of energy metabolism, 2) reduction of energy ‘subsidization’ with autophagy inhibitors, 3) acceleration of ATP turnover to increase energy inefficiency, and 4) dietary energy restriction to limit the energy supply.

Follow the ATP: Tumor Energy Production: A PerspectiveDownload

The article outlines several compounds (many that have been outlined here) that can be exploited to upset the tumor “economy” and bring about therapeutic benefit.

Must Read Cancer Books

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

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 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

Noscapine Induces Apoptosis in Human Colon Cancer Cells by Regulating Mitochondrial Damage and Warburg Effect via PTEN/PI3K/mTOR Signaling Pathway

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

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

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

Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS–STAT3 pathway

Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells

Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer

Piperlongumine induces apoptotic and autophagic death of the primary myeloid leukemia cells from patients via activation of ROS-p38/JNK pathways

Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells

New Mild and Simple Approach to Isothiocyanates: A Class of Potent Anticancer Agents

Targeting p53-deficient chronic lymphocytic leukemia cells in vitro and in vivo by ROS-mediated mechanism

Effective elimination of chronic lymphocytic leukemia cells in the stromal microenvironment by a novel drug combination strategy using redox-mediated mechanisms

Long Pepper 500mg/Capsule – Piperlongumine

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

“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.

Meet the BCL-2 Family

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

The BCL-2 Family Reunion

Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia

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 – 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