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
“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:
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 cross hairs
- Tagged Apoptosis, BCL2, BH3 Mimetic, Cancer, CLL, DCA, Glutathione, Methyl Jasmonate, mitochondrial permeability transition, Natural, PEITC, Reactive Oxygen Species
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 induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa
Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol
- Tagged Apoptosis, Cancer, CLL, Glutathione, Mitocan, Mitochondria, mitochondrial outer membrane permeabilization, Natural, PEITC, Reactive Oxygen Species, Redox