Trends in Cell Biology
ReviewSpecial Issue: Translational Cell BiologyMitochondria: gatekeepers of response to chemotherapy
Section snippets
Why does chemotherapy work?
A longstanding question among not only patients but also the oncologists that are treating them is ‘why does chemotherapy work?’ This important question is asked because chemotherapy does, at times, work impressively well, leading to long-term cures of otherwise fatal neoplasms. However, despite growing understanding of how cancers arise, grow, metastasize, and eventually overcome the host, the mechanisms behind successful treatment of cancers are poorly understood 1, 2. The key determinants of
Chemotherapy and apoptosis
Treatment of human malignancies with chemotherapy with curative intent has been successfully conducted for over 50 years, with millions of cancer survivors enjoying long lives after treatment [3]. However, millions more have succumbed to their disease. Regardless of whether they are considered ‘cytotoxic’ or ‘targeted’, most chemotherapies function by inducing a form of irreversible programmed cell death called apoptosis 4, 5, 6, 7. Apoptosis can proceed via two distinct pathways: intrinsic and
Measuring mitochondrial apoptotic priming
Regulation of the balance of pro- and antiapoptotic proteins within cells, and thus how close a cell is to the threshold of apoptosis, is dependent on many factors. To avoid apoptosis, a cell must express a sufficient amount of antiapoptotic proteins to bind and inactivate what proapoptotic counterparts are also present. Furthermore, most cells contain an additional amount of ‘buffering’ antiapoptotic proteins that can inactivate further pro-death signals that are encountered on a stochastic
Mitochondrial apoptotic priming determines tumor response to cytotoxic chemotherapy
Using BH3 profiling to measure levels of apoptotic priming across a range of cancer types, it has been shown that primed cells readily undergo apoptosis in response to cytotoxic chemotherapy whereas unprimed cells are less likely to do so (Table 1) [5]. Notably, this holds true not only in cancer cell lines but also in primary tumors and can be predictive of how patients will respond to chemotherapy in the clinic 5, 29. In addition, cells within tumors that have undergone treatment and then
What determines how primed a tumor will be?
Although cancers have wide-ranging levels of mitochondrial priming that contribute to their responses to chemotherapeutic agents 5, 28, 29, it is unclear what determines the level of priming within a cell or tumor. At the cellular level, an attractive hypothesis is that the level of priming evident in a tumor cell is determined, at least in part, by the level of priming evident in the cell that gave rise to the tumor itself. Lending evidence to this concept is the observation that the most
The chemotherapeutic window
Understanding the mitochondrial priming of the tumor alone, however, is insufficient to understanding the source of a chemotherapeutic window. The key to achieving a desirable outcome from chemotherapy is as much dependent on the lack of priming in vital organs as the priming in the tumor. When comparing apoptotic priming across healthy tissues, one can see that most healthy tissues are unprimed, which allows vital organs such as the liver, heart, brain, and kidneys to survive high doses of
Mitochondria in targeted chemotherapies and immunochemotherapies
Mitochondrial priming also has a likely role in the cellular response to targeted chemotherapies. Although ‘classical’ cytotoxic chemotherapies can have quite specific targets (e.g., paclitaxel for microtubules, topotecan for topoisomerase II), for the purpose of this review only agents that target non-ubiquitous cellular components are considered targeted agents. Much progress has been recently made in the development of targeted agents that have the potential to be selectively toxic to cancer
Alternative determinants of chemotherapy effectiveness
Although recent results have suggested that priming is the major determinant of chemotherapy effectiveness 5, 28, 29, several laboratories have provided evidence of alternatives. In mitochondria specifically, chemotherapy response has been linked to defects in mitochondrial respiratory chain complexes caused by loss of specific cytochrome c oxidase subunits [70]. The loss of these subunits was observed clinically in a subset of esophageal adenocarcinomas and was associated with increased
Concluding remarks
Mitochondria have a well-established and prominent role in chemotherapy effectiveness that should be exploited for cancer therapy. Specifically targeting the BCL-2 family is a strategy that has already shown promise; the BCL-2/BCL-XL/BCL-w inhibitor ABT-737 and its derivatives have activity against multiple types of blood cancer [64] and some solid tumors 76, 77, 78. Other strategies to inhibit these proteins are also in various stages of preclinical development (reviewed in [79]). One
Acknowledgments
The authors acknowledge the many researchers who contributed to our understanding of mitochondria, apoptosis, and cancer biology and apologize that we could not cite all of the relevant research due to space restrictions. They gratefully acknowledge funding from the American Cancer Society Postdoctoral Fellowship 121360-PF-11-256-01-TBG (K.A.S.), the Women's Cancers Program at the Dana-Farber Cancer Institute (A.L.), and NIH grants RO1CA129974 (A.L.) and P01CA139980 (A.L). A.L. is a Leukemia
References (89)
Apoptosis: a link between cancer genetics and chemotherapy
Cell
(2002)- et al.
Induction of apoptosis by cancer chemotherapy
Exp. Cell Res.
(2000) The BCL-2 family reunion
Mol. Cell
(2010)Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis
Cell
(2013)Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Cancer Cell
(2002)Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis
Mol. Cell
(2009)GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation
Cell
(2007)BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents
Cancer Cell
(2007)Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia
Blood
(2012)Relative mitochondrial priming of malignant myeloblasts and normal HSCs determines chemotherapeutic success in AML
Cell
(2012)
The hallmarks of cancer
Cell
Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma
Blood
Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy
Blood
Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer
Cell
In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death
Cell
PI3 kinase signals BCR-dependent mature B cell survival
Cell
Targeting the PI3K signaling pathway in cancer
Curr. Opin. Genet. Dev.
Distinct thresholds govern Myc's biological output in vivo
Cancer Cell
Induction of apoptosis by c-myc protein in fibroblasts
Cell
Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas
Blood
Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia
Blood
Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells
Cancer Cell
CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma
Blood
BH3 mimetics to improve cancer therapy; mechanisms and examples
Drug Resist. Updat.
A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival
Chem. Biol.
cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity
Blood
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
Lancet Oncol.
Defying death after DNA damage
Nature
Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy
Oncogene
Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care
Cancer Epidemiol. Biomarkers Prev.
Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy
Science
BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response
Mol. Cell
Mitochondria and cell death: outer membrane permeabilization and beyond
Nat. Rev. Mol. Cell Biol.
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies
Nat. Cell Biol.
Direct activation of full-length proapoptotic BAK
Proc. Natl. Acad. Sci. U.S.A.
BAX activation is initiated at a novel interaction site
Nature
tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c
Genes Dev.
Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak
Science
BID-induced structural changes in BAK promote apoptosis
Nat. Struct. Mol. Biol.
Caspase-independent mitochondrial cell death results from loss of respiration, not cytotoxic protein release
Mol. Biol. Cell
Apoptosis in the development and maintenance of the immune system
Nat. Immunol.
Restricting apoptosis for postmitotic cell survival and its relevance to cancer
Cell Cycle
Epigenetic events in mammalian germ-cell development: reprogramming and beyond
Nat. Rev. Genet.
BH3 profiling in whole cells by fluorimeter or FACS
Methods
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