Trends in Cell Biology
Volume 23, Issue 12, December 2013, Pages 612-619
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Review
Special Issue: Translational Cell Biology
Mitochondria: gatekeepers of response to chemotherapy

https://doi.org/10.1016/j.tcb.2013.08.003Get rights and content

Highlights

  • Mitochondrial apoptotic priming determines cellular response to chemotherapy.

  • The chemotherapeutic window is based on differential levels of mitochondrial priming.

  • Mitochondrial priming can be modulated to improve chemotherapy response.

Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some cancers are sensitive to chemotherapy whereas others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies.

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

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