Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles

JNCI: Journal of the National Cancer Institute, Nov 2017

Emadi, Ashkan, Lapidus, Rena G

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Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles

JNCI J Natl Cancer Inst ( Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles Ashkan Emadi 0 1 2 Rena G. Lapidus 0 1 2 0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please 1 Room N9E24 , Baltimore, Maryland 21201 , USA 2 Affiliation of authors: University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center , Baltimore, MD , USA - Many malignant cells exhibit the Warburg effect, first described by Otto Warburg in 1924 ( 1 ). Since then, this phenomenon has been well documented and characterized by augmented aerobic glucose uptake, glycolytic shift, decreased utilization of pyruvate by mitochondria, and increased lactate production, all of which are mainly controlled by hypoxia-induced factor 1 alpha (HIF-1a) and Myc overexpression in neoplastic cells ( 1 ). HIF-1a and Myc attenuate mitochondrial function by activating pyruvate dehydrogenase kinases (PDKs), which phosphorylate and inactivate the pyruvate dehydrogenase complex (PDC). Hence, inhibiting the PDKs can shuttle more pyruvate into mitochondrial oxidative phosphorylation and away from lactate synthesis, resulting in oxidative stress, triggering apoptosis, and augmentating host immuno-surveillance, ultimately leading to diminished tumor proliferation ( 2 ). Additionally, the Warburg effect leads to increased lactate in cellular and extracellular compartments. This three-carbon acidic molecule induces a cascade of events that leads to growth advantage of cancer cells, angiogenesis, evasion of the immune system, and possibly resistance to radiation therapy. In this issue of the Journal, Stacpoole provides a review on biochemistry of the mitochondrial enzymatic machinery PDC and its master regulator PDKs and their exploitation for treatment of solid and hematologic neoplasms ( 3 ). The reviews of structure and regulation of the PDC as well as PDC/PDK axis in cancer and the corresponding figures are comprehensive and well described. In essence, the review describes how to target the unique metabolic requirements in a cancer cell via PDC and its key regulatory enzyme, PDK, that when inhibited can shut down the metabolic advantage that a cancer cell requires for growth. Lastly, Stacpoole makes the important observation that solid tumors are heterogeneous; in relation to the current discussion, glycolysis and oxidative phosphorylation could both be occurring simultaneously in a tumor, causing metabolism to be a moving target for therapeutic intervention. Several PDK inhibitors have been discussed. The most commonly used “mitochondrial awakening” agent is dichloroacetate (DCA) sodium, which has been investigated preclinically and clinically for a variety of metabolic and neoplastic disorders in the last three decades. DCA is a weak antineoplastic agent with IC50s in the millimolar range, albeit it is reported to be well tolerated in early phase clinical trials with relatively well known pharmacodynamics and pharmacokinetic characteristics ( 4 ). To improve the cytotoxicity of DCA, investigators have synthesized compounds in which several DCA molecules are attached to platinum chemotherapeutics, betulinic acid, tertiary amines, hemoglobin, phosphorium cations, etc., with IC50s in micromolar range. Non-DCA-based PDK inhibitors with nanomolar IC50s have been synthesized by pharmaceutical companies and are currently under investigation. There is an absolute need for more robust preclinical investigations on PDK inhibition and its effect on increasing the sensitivity of immune cells to neoplastic cells, or on glutamine metabolism, or on histone modification and epigenetic modulation, etc. A concerted effort should be made to further test DCA and its mimetics in combination with both known and experimental agents to enhance their antineoplastic effects by taking advantage of synergistic mechanisms of action ( 5 ). Interestingly, circulating lactate declines after DCA administration; thus, lactate may be an excellent biomarker for not only DCA treatment but other PDK inhibitors. Nevertheless, to date, none of the available PDK inhibitors has been approved for use in humans by the US Food and Drug Administration. The main reason is the lack of evidence for providing meaningful clinical benefit for patients with malignant diseases in well-designed, well-conducted clinical trials. Although targeting the Warburg effect and mitochondrial function is like an old wine, now, it is time to pour it into new bottles; academic and pharmaceutical translational, clinical and regulatory scientists should collaborate to perform clinical studies that involve novel molecules with innovative end points that have clear regulatory pathways for expedited drug approval for newer PDC/PDK inhibitors. Such trials can combine PDC/PDK inhibitors with contemporary immunotherapeutic agents such as PD-1/PD-L1 inhibitors, or inhibitors of Src that directly phosphorylate tyrosine residues on the E1a subunit of PDC independent of PDK expression, or epigenetic modulators, or inhibitors of antioxidants, or liposomal encapsulation and delivery, to name a few combinations. Investigators can use serum or tumor lactate levels as a biomarker for therapeutic response to these new treatments. Such approaches can benefit from lower doses of PDC/PDK inhibitors that are still efficacious but better tolerated. The authors are both inventors on patent number “9,381,215” entitled “Compositions and methods for the treatment of cancers” assigned to the University of Maryland. 1. Koppenol WH , Bounds PL , Dang CV . Otto Warburg's contributions to current concepts of cancer metabolism . Nat Rev Cancer . 2011 ; 11 ( 5 ): 325 - 337 . 2. Saunier E , Benelli C , Bortoli S. The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents . Int J Cancer . 2016 ; 138 ( 4 ): 809 - 817 . 3. Stacpoole PW . Therapeutic targeting of the pyruvate dehydrogenase complex/ pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer . J Natl Cancer Inst . 2017 ; 109 ( 11 ): djx071 . 4. James MO , Jahn SC , Zhong G , et al. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1 . Pharmacol Ther . 2016 ; 170 : 166 - 180 . 5. Emadi A , Sadowska M , Carter-Cooper B , et al. Perturbation of cellular oxidative state induced by dichloroacetate and arsenic trioxide for treatment of acute myeloid leukemia . Leuk Res . 2015 ; 39 ( 7 ): 719 - 729 .

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Emadi, Ashkan, Lapidus, Rena G. Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles, JNCI: Journal of the National Cancer Institute, 2017, DOI: 10.1093/jnci/djx069