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…”
“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
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