**5. DCA, attempting to reverse tumor-specific PDK repression of PDH activity**

Dichloroacetate (DCA) is a small molecule with a long history of clinical use for treatment of elevated serum lactate levels in some inherited metabolic conditions [62]. Moreover, DCA is well characterized as being a non-metabolizable pyruvate analog that can strongly inhibit PDK function [17,22, 63] .Thus, DCA is a candidate to reverse PDK repression of PDH important to cancer cell tumorigenicity (above).

These considerations influenced Bonnet [1] to investigate DCA's potential anti-cancer effects. These authors observed that DCA treatment could reverse the mitochondrial membrane hyper-polarization characteristic of tumor cells without noticeable effect on the lower level of polarization in normal cells. Further, DCA substantially increased glucose oxidation while decreasing fatty acid oxidation in A549 tumors cells [1]. These and other effects correlate with DCA inhibition of cancer cell growth and induction of a modest increase in the rate of cancer cell apoptosis. Finally and most importantly, DCA very significantly inhibits tumor growth in mouse xenograft models. Specifically, DCA administered ad libitum in drinking water at 75mg/l produced both inhibition of xenograft tumor growth and modest, but significant reduction in tumor volume in larger tumors. Subsequent reports from other groups corroborate these preclinical findings [64, 65].

50 Dehydrogenases

this drug resistance.

qualitatively unique to tumor cells.

important to cancer cell tumorigenicity (above).

**activity** 

agents. Finally, Lu, et al. [58] observed that both PDK1 and PDK3 collaborated to produce

Collectively, these results clearly indicate that PDK regulation of PDH activity is central to the malignant phenotype. Moreover, there is apparently no metabolic bypass of the requirement for properly managed mitochondrial metabolism. Mitochondria are not turned off in hypoxic tumor cells. Rather, they are redeployed to provide the limited carbon traffic they can sustain to the provision of anabolic intermediates (above). There appears to be no other way to provide some of these biosynthetic resources (citrate for lipid biosynthesis, for example). Further, mitochondria are central controllers of Ca++ signaling [see 59 and references therein] and of cell death control as reviewed in [60,61]. Thus, their continued properly controlled function is likely to be essential to cancer cell homeostasis and survival. These results and considerations are consistent with the hypothesis that this re-regulation of PDH cannot be dispensed with. Without this metabolic pattern cancer cells are likely to be unable to survive and prosper in the hypoxic environment crucial to malignant progression. Thus, PDK re-regulation is a candidate for the kind of essential, non-redundant therapeutic target needed if we are to have fundamentally new clinical options. We will argue below

Before turning to assessment of how we might attack this potential target it is important to emphasize a particular implication of PDK re-regulation in cancer cells. Because of the possibility of PDK heterodimer formation (above), tumor-specific quantitative changes in individual PDK expression may be substantially amplified in their regulatory effects. For example, if PDK1 and PDK3 were both up-regulated 10 fold in the *in vivo* tumor environment, this could represent a 100-fold increase in the levels of the hypothetical PDK1/PDK3 heterodimer. Such very large effects might represent targets that are essentially

**5. DCA, attempting to reverse tumor-specific PDK repression of PDH** 

Dichloroacetate (DCA) is a small molecule with a long history of clinical use for treatment of elevated serum lactate levels in some inherited metabolic conditions [62]. Moreover, DCA is well characterized as being a non-metabolizable pyruvate analog that can strongly inhibit PDK function [17,22, 63] .Thus, DCA is a candidate to reverse PDK repression of PDH

These considerations influenced Bonnet [1] to investigate DCA's potential anti-cancer effects. These authors observed that DCA treatment could reverse the mitochondrial membrane hyper-polarization characteristic of tumor cells without noticeable effect on the lower level of polarization in normal cells. Further, DCA substantially increased glucose oxidation while decreasing fatty acid oxidation in A549 tumors cells [1]. These and other effects correlate with DCA inhibition of cancer cell growth and induction of a modest increase in the rate of cancer cell apoptosis. Finally and most importantly, DCA very

that this target can be therapeutically exploited in several different ways.

The clinical follow up on these preclinical results has been generally weak. This largely results from economic factors. DCA is a cheap, generic drug and no corporate actors have an incentive to develop the agent. To date clinical data consist of several anecdotal case reports [66,67] suggesting possible efficacy, including in a poorly differentiated metastatic carcinoma. In addition, in view of its low cost and wide availability, DCA is being prescribed off-label or self- administered. Anecdotal reports of efficacy from this use group can be found in patient/physician webshops (see, for example, www.thedcasite.com). It will be of considerable interest to see if sufficient evidence can be accumulated to assess the clinical potential of this agent.

An apparently common side effect of DCA use is peripheral neuropathy. Though this is generally limited and reversible, this may not always be the case. A patient report describes relatively severe encephalopathy probably induced by DCA doses within the range currently being experimented with by patients and their physicians [68]. These problems emphasize the importance for individual patients of using DCA only under professional medical supervision.

Finally, a series of small molecule PDK inhibitors have been developed, initially for the treatment of diabetes as reviewed in [8]. These compounds are far more potent than DCA on a mole basis and it will be of interest to see if they have significant anti-cancer activity. To date, no clinical trial data are available on any possible anti-cancer activities of these agents. Moreover, the design strategy for these compounds renders them relatively selective for individual PDK homodimers. We do not currently know which homo- or heterodimer(s) might be the most propitious anti-cancer target(s) for this class of agents.
