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Due to this metabolic change and the decrease of mitochondrial depolarization, cancer cells have a survival advantage and are not affected by intrinsic apoptosis pathways 29 , For preclinical assessment of anticancer drugs in vitro experiments with cell lines are important approaches in human as well as in veterinary research. In vitro investigations offer the possibility to receive more information on efficaciousness and sensitivity of several tumor entities 31 — In this study several established 34 and new cell lines were used.
To our knowledge this is the first study in which the effect of DCA on canine prostate adenocarcinoma and transitional cell carcinoma TCC cells have been investigated. The influence of DCA on cell counts, lactate levels, mitochondrial activity, apoptosis and metabolic activity was determined.
Further there is no literature on the influence of DCA on bladder cancer in human or in veterinary medicine. The cell lines were classified as prostate adenocarcinoma or TCC after pathohistological examination of the initial tissues. DCA was dissolved in deionized water, filter-sterilized and pH was adjusted to 7. The dosis of 10 mM was selected according to previous studies with human HeLa cells Even if this concentration might not be safely reached in vivo , this concentration was chosen to allow the comparability to other human in vitro studies.
For lactate level measurements supernatant from cell culture was centrifuged at 1, rpm for 10 min to remove floating cells and debris and 1. To eliminate alterations due to phenol red and lactate natively from fetal calf serum, medium was used as negative control and deducted from measurements. Measurements were performed every 24 h over a period of four days. After this period, cells were trypsinized and centrifuged together with medium containing non-adherent and dead cells at 1, rpm for 6 min.
Annexin and Sytox were detected in FL Data analysis was performed with FlowJo Version Gates were set by mean of positive controls cells permeabilized with Saponin and negative controls of each cell line non-treated viable cells. Relative quantification of microRNA expression of treated cells in comparison to negative control was performed with Eppendorf realplex 4 Cycler Eppendorf, Wesseling-Berzdorf, Germany using 1.
Additionally, samples for PDH measurements were filtered with centrifugal ultrafree filter units with a pore size of 0. Images were taken with EZ-C1 1. Total cell fluorescence of MitoSox deducting background was analyzed with ImageJ and normalized to cell counts. Cells were seeded, fixed and washed as described above. After washing with HBSS, cells were permeabilized with 0.
Fluorescence imaging protocol was the same as described above. Total cell fluorescence was established as described above. The excitation occurred with an argonlaser at nm and imaging was performed as described above. Statistical analysis of data was performed with SAS software 7.
For comparison of two means, two-tailed t-test was used. As shown in Fig. Effect of 10 mM DCA on different canine cancer cells after 48 h. A Canine prostate adenocarcinoma cell lines. B Canine transitional cell carcinoma cell lines. To assess the lactate release lowering effect of DCA treatment after 48 h, lactate amount in cell culture supernatant was measured, respectively. In all cell lines of both canine cancer entities, 10 mM DCA had a significant lactate lowering effect Fig.
Effect of 10 mM DCA on lactate levels after 48 h in supernatant of cell culture. After DCA treatment lactate levels decreased significantly in all cell lines. To confirm the negative effect on cell proliferation, the metabolic activity as indicator for proliferation and cell viability was analyzed by MTT assays. In course of time the metabolic activity decreased slightly within 24 h and reached significance after 96 h.
Cell proliferation in 10 mM DCA exposed cell lines were analyzed by Ki67 staining and visualized by confocal fluorescence microscopy. Effect of 10 mM DCA on cell proliferation with confocal fluorescence microscopy after 48 h. Significantly decreased amounts of Ki67 thus proliferation was determined in all cell lines. The fluorescence images display decreased total cell fluorescence of Ki67 positive cells compared to non-treated control A-D.
E Canine prostate adenocarcinoma cell lines. F Canine transitional cell carcinoma cell lines. Regarding apoptosis and dead cells no statistical significant effects were noted in any of the cell lines data not shown. Imaging was performed using confocal fluorescence microscopy. The other cell lines displayed no significant apoptosis values. Effect of 10 mM DCA on survivin expression in supernatant after 48 h. The same cells were injected in the flank of nude rats. It is important here to clarify that simply inhibiting GLY, will not promote pyruvate entry into the mitochondria, that is, it will not re-activate mitochondria.
It will also be toxic to several non-cancerous tissues that depend on GLY for energy production. Inhibiting GLY which has previously been tested as a potential treatment for cancer results in ATP depletion and necrosis, not apoptosis, because apoptosis is an energy-consuming process, requiring active mitochondria Xu et al, This hypothesis is also supported by the recently published work that inhibition of LDH by siRNA , which promotes the transfer of pyruvate into the mitochondria in that sense mimicking DCA , also promotes cancer apoptosis and decreases tumour growth in vitro and in mice xenotransplants Fantin et al, To date, four different isoforms of PDK have been identified that have variable expression and sensitivity to the inhibition by DCA Sugden and Holness, The end point measured was the decrease in lactate levels in both the blood and the cerebrospinal fluid.
Although the pharmacokinetics of DCA in healthy volunteers follow a simple one-compartment model, they are more complex in severely abnormal states like severe lactic acidosis or cirrhosis. Dichloroacetate inhibits its own metabolism by an unknown mechanism, and the clearance of DCA decreases after multiple doses Stacpoole et al, Although the initial half-life with the first dose is less than one hour, this half-life increases to several hours with subsequent doses.
However, there is a plateau of this effect and DCA serum levels do not continue to rise with chronic use. A large number of children and adults have been exposed to DCA over the past 40 years, including healthy volunteers and subjects with diverse disease states. Since its first description in Stacpoole, , DCA has been studied to alleviate the symptoms or the haemodynamic consequences of the lactic acidosis complicating severe malaria, sepsis, congestive heart failure, burns, cirrhosis, liver transplantation and congenital mitochondrial diseases.
Single-arm and randomised trials of DCA used doses ranging from Although DCA was universally effective in lowering lactate levels, it did not alter the course of the primary disease for example sepsis. More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study.
Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination.
No other toxicities were reported. It is important to note that peripheral neuropathy often complicates MELAS because of primary or secondary effects on peripheral nerves; for example these patients also have diabetes and diabetes-related peripheral neuropathy. In contrast, another randomised placebo-controlled double-blinded study failed to show any significant toxicity of DCA, including peripheral neuropathy.
Serial nerve conduction studies failed to demonstrate any difference in incidence of neuropathy in the 2 arms placebo vs DCA. Sleepiness and lethargy, muscular rigidity of the upper extremity and hand tremor were reported in one patient in each group Stacpoole et al, The higher incidence of peripheral neuropathy in adult MELAS patients may represent an intrinsic predisposition to this complication in MELAS or its associated conditions, that is, diabetes mellitus; this toxicity might also be age-dependent.
In summary, peripheral neuropathy is a potential side effect of DCA that appears to be largely reversible. As peripheral neuropathy is a frequent complication of taxane, platinum and vinca-alkaloid chemotherapies, the risk for DCA-associated peripheral neuropathy may depend on whether cancer patients have prior or concurrent neurotoxic therapy.
There is substantial evidence in preclinical in vitro and in vivo models that DCA might be beneficial in human cancer Bonnet et al, ; Cairns et al, ; Cao et al, ; Wong et al, The concept is strengthened by the fact that LDH inhibition in mice with human cancer xenotransplants, also induced apoptosis and inhibited growth, improving survival Fantin et al, There is also 40 years of human experience with mechanistic studies of DCA in human tissues after oral use, pharmacokinetic and toxicity data from randomised studies for 6 months, and 5-year use case reports.
This supports an easy translation to early-phase clinical trials. Dichloroacetate could be tested in a variety of cancer types.
However, direct preclinical evidence of anticancer effects of DCA has been published only with non-small cell lung cancer, glioblastoma and breast, endometrial and prostate cancer. In addition, the lack of mitochondrial hyperpolarisation in certain types of cancer, including oat cell lung cancer, lymphomas, neuroblastomas and sarcomas Chen, , suggest that DCA might not be effective in such cases. Cancers with limited or no meaningful therapeutic options like recurrent glioblastoma or advanced lung cancer should be on top of the list of cancers to be studied.
No patient with cancer has received DCA within a clinical trial. It is unknown whether previously studied dose ranges will achieve cytotoxic intra-tumoral concentrations of DCA.
In addition, the overall nutritional and metabolic profile of patients with advanced cancer differs from those in the published DCA studies. Furthermore, pre-exposure to neurotoxic chemotherapy may predispose to DCA neurotoxicity. Carefully performed phase I dose escalation and phase II trials with serial tissue biopsies are required to define the maximally tolerated, and biologically active dose. Clinical trials with DCA will need to carefully monitor neurotoxicity and establish clear dose-reduction strategies to manage toxicities.
Furthermore, the pharmacokinetics in the cancer population will need to be defined. The preclinical experience with DCA monotherapy warrants clinical trials with DCA as a single agent or in direct comparison with other agents. In that sense, DCA could both precede and be given concurrently with chemotherapy or radiation therapy, in an attempt to increase their effectiveness, decrease the required doses and limit the toxicity of standard therapies Cairns et al, The ability to approach metabolism as an integrator of many diverse signalling pathways, prompts consideration of the imaging and diagnostic studies that might track metabolic modulation.
As discussed above, important questions that need to be answered in clinical trials using DCA include: i can PET be used as a predictor of clinical response or as a means of documenting non-invasively a reversal of the glycolytic phenotype in response to DCA? Funding for such trials would be a challenge for the academic community as DCA is a generic drug and early industry support might be limited.
However, if these trials suggest a favourable efficacy and toxicity, the public will be further motivated to directly fund these efforts and national cancer organisations like the NCI, might be inspired to directly contribute to the design and structure of larger trials. In that sense, the clinical evaluation of DCA, in addition to its scientific rationale, will be by itself another paradigm shift.
Since the acceptance of this review two important papers have confirmed the novel anticancer effects of DCA in prostate and endometrial cancers: Wong JY et al , Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol June ; 3 : — and Gao et al , Dichloroacetate DCA sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.
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