“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”.
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”.
Once again we have natural compounds that have strong anti-cancer activity and effect multiple pathways. There’s quite a bit of overlap between these two, but also some antagonism as well, so if you decide to supplement these pay attention to the required dosing schedule.
“Constitutively activated pathways contribute to apoptosis resistance in chronic lymphocytic leukemia (CLL). Little is known about the metabolism of lipids and function of lipases in CLL cells. Performing gene expression profiling including B-cell receptor (BCR) stimulation of CLL cells in comparison to healthy donor CD5+ B cells, we found significant overexpression of lipases and phospholipases in CLL cells. In addition, we observed that the recently defined prognostic factor lipoprotein lipase (LPL) is induced by stimulation of BCR in CLL cells but not in CD5+ normal B cells. CLL cellular lysates exhibited significantly higher lipase activity compared to healthy donor controls. Incubation of primary CLL cells (n=26) with the lipase inhibitor orlistat resulted in induction of apoptosis, with a half-maximal dose (IC50) of 2.35 mum. In healthy B cells a significantly higher mean IC50 of 148.5 mum of orlistat was observed, while no apoptosis was induced in healthy peripheral blood mononuclear cells (PBMCs; P<0.001). Orlistat-mediated cytotoxicity was decreased by BCR stimulation. Finally, the cytotoxic effects of orlistat on primary CLL cells were enhanced by the simultaneous incubation with fludarabine (P=0.003). In summary, alterations of lipid metabolism are involved in CLL pathogenesis and might represent a novel therapeutic target in CLL”. Follow the link: Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of B-cell chronic lymphocytic leukemia cells
Watercress has it. So does cauliflower, cabbage, bok choy, broccoli, and brussels sprouts. Phenethyl Isothiocyanate (PEITC) is another powerful, natural anti-cancer compound. It works by manipulating redox status in the cell. Follow the links for some of the research on this powerful glutathione inhibitor.
Update: Follow the link for a nice primer on apoptosis, BCL-2, and BH3 Mimetics.
Dr. Sharman’s CLL & Lymphoma Blog – What is BCL-2 and why should we inhibit it?
“Chronic lymphocytic leukemia (CLL) is characterized by the deregulated accumulation and persistence of B lymphocytes in the blood. Although the exact causes of CLL are unknown, the evasion of apoptosis through aberrant expression of BCL2-family proteins is a common feature. A class of compounds, termed BH3 mimetics, has been developed to directly inhibit BCL2 proteins and selectively kill tumor cells. To date, the most successful of these compounds are the BCL2/BCLXL inhibitors ABT-7372 and ABT-263 (navitoclax), as well as the BCL2-specific inhibitor ABT-199. Results from early clinical trials with navitoclax have demonstrated single-agent efficacy in patients with relapsed or refractory CLL.
However, there was heterogeneity in response rates between patients, and dose-limiting toxicities including thrombocytopenia and neutropenia which prevented further doseescalation.
In addition, CLL cells residing within various microenvironments (e.g. lymph nodes and bone marrow) are resistant to BCL2 inhibitors. This resistance results from the upregulation of additional BCL2-proteins, such as BCLXL, MCL1 and BFL1, the latter two of which are not inhibited by navitoclax, and therefore protect the leukemia cells from apoptosis. Additional drugs are needed to enhance the efficacy of navitoclax. Here, we demonstrate that gossypol overcomes stroma-mediated resistance to ABT-737 without enhancing the sensitivity of normal lymphocytes and platelets.
The BH3-only protein, NOXA, is a potent inhibitor of MCL1 and BFL1, but has recently been recognized to inhibit BCLXL with lower affinity. Therefore, compounds which induce NOXA may inhibit MCL1, BFL1 and BCLXL, thus overcoming resistance to navitoclax. We previously reported that six putative BH3 mimetics do not directly inhibit BCL2 in cells, but instead activate the integrated stress response and induce NOXA. Of these six compounds, gossypol has advanced into clinical trials in a racemically purified form (AT-101).10 We hypothesized that gossypol, through induction of NOXA, would sensitize CLL cells to ABT-737”. Link below:
“In mammals, apoptosis occurs through the death receptor (extrinsic) or Bcl-2-regulated (intrinsic or mitochondrial) pathways. The latter is regulated by three subgroups of the Bcl-2 family: the pro-survival members, such as BCL-2 or MCL1, the pro-apoptotic BAX and Bcl-2 homologous killer (BAK) subgroup and the pro-apoptotic BCL-2 homology domain 3 (BH3)-only proteins, such as BIM (also known as BCL2L11) and PUMA (also known as BBC3). Apoptotic stimuli cause transcriptional and/or post-translational activation of specific BH3-only proteins, which then engage and sequester the pro-survival Bcl-2 family members, thereby liberating the downstream effectors, BAX and BAK, which elicit mitochondrial outer membrane permeabilization (MOMP) and unleash the caspase cascade, culminating in cell demolition. It has also been proposed that at least some BH3-only proteins, in particular BIM and BID, can directly activate BAX and BAK (not shown). Some BH3-only proteins (shown in green), such as BIM and PUMA, can bind and sequester all anti-apoptotic Bcl-2 family members with high affinity and are thus potent killers, whereas others (shown in yellow and dark pink), such as Bcl-2 antagonist of cell death (BAD) and NOXA (also known as PMAIP1), bind only certain anti-apoptotic members (BAD binds BCL-2, BCL-XL and BCL-W (dark blue), whereas NOXA binds only MCL1 and A1 (light blue)). Thus, the efficiency of cell killing is determined by the relative levels of pro- and anti-apoptotic members. ABT-737, a BH3-mimetic, has a similar binding profile to the BH3-only protein BAD. APAF1, apoptotic protease-activating factor 1; BMF, Bcl-2-modifying factor; HRK, activator of apoptosis harakiri; tBID, truncated BID.”
Methyl Jasmonate is a plant stress hormone that has significant anti-cancer properties. So how does MJ work? Let me count the ways. It arrests cell cycle, inhibiting cell growth and proliferation; causes cell death through the intrinsic/extrinsic pro-apoptotic, p53-independent apoptotic, and non-apoptotic (necrosis) pathways; detaches hexokinase from the voltage-dependent anion channel, dissociating glycolytic and mitochondrial functions, decreasing the mitochondrial membrane potential, favoring cytochrome c release and ATP depletion, activating pro-apoptotic and inactivating anti-apoptotic proteins; induces reactive oxygen species mediated responses; stimulates MAPK-stress signaling and redifferentiation in leukemia cells; inhibits overexpressed pro-inflammatory enzymes in cancer cells such as aldo-keto reductase 1 and 5-lipoxygenase; inhibits cell migration and shows antiangiogenic and anti-metastatic activities. The complete lack of toxicity to normal cells and the rapidity by which MJ causes damage to cancer cells, turns MJ into a promising anticancer agent that can be used alone or in combination with other agents.
Follow the links for the relevant research: