phosphocreatine and Breast-Neoplasms

Creatine is a nitrogen-containing organic acid naturally existing in mammals. It can be converted into phosphocreatine to provide energy for muscle and nerve tissues. Creatine and its analog, cyclocreatine, have been considered cancer suppressive metabolites due to their effects on suppression of subcutaneous cancer growth. Recently, emerging studies have demonstrated the promoting effect of creatine on cancer metastasis. Orthotopic mouse models revealed that creatine promoted invasion and metastasis of pancreatic cancer, colorectal cancer, and breast cancer. Thus, creatine possesses considerably complicated roles in cancer progression. In this review, we systematically summarized the role of creatine in tumor progression, which will call to caution when considering creatine supplementation to clinically treat cancer patients.

Topics: Animals; Breast Neoplasms; Creatine; Female; Humans; Mammals; Mice; Phosphocreatine

The 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is widely used in the management of breast cancer. The common cardiotoxic effects of doxorubicin include congestive heart failure and left ventricular dysfunction, and those of cyclophosphamide include pericarditis, myocarditis, and congestive heart failure. It has been postulated that cardiotoxicity of 5-fluorouracil presents as coronary artery diseases (eg, angina). Cardiomyopathy is a common outcome following treatment with the FAC regimen. We report on a 52-year-old woman with cardiomyopathy following chemotherapy and radiation therapy. The patient did not respond well to b-blockers and angiotensin-converting enzyme inhibitors. After the addition of exogenous phosphocreatine, the patient's cardiac condition improved significantly.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiomyopathies; Cardiotoxicity; Cyclophosphamide; Doxorubicin; Electrocardiography; Female; Fluorouracil; Humans; Middle Aged; Phosphocreatine; Tomography, X-Ray Computed; Treatment Outcome

Drug resistance is a prominent problem of cancer therapy. Differences in quantity and quality of many metabolites in normal and malignant cells and their changes after treatment by anticancer drugs can be detected by nuclear magnetic resonance (NMR) both in vivo and in vitro. The results of in vivo and in vitro 1H, 13C, 19F and 31P NMR spectroscopy and their correlation with the degree of resistance to anticancer drugs are discussed. Monitoring of treatment and development of drug resistance by this non-invasive method could be useful not only in cancer research related to drug resistance but also in clinical medical oncology.

Topics: Amino Acids; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carbon Isotopes; Creatinine; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Energy Metabolism; Female; Fluorine; Humans; Isotopes; Lactates; Lipids; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Neoplasm Proteins; Phosphocreatine; Phosphorus Isotopes; Tumor Cells, Cultured

Topics: Adenosine Triphosphate; Blood Flow Velocity; Body Fluids; Breast Neoplasms; Energy Metabolism; Female; Humans; Hydrogen-Ion Concentration; Oxygen; Oxygen Consumption; Phosphocreatine; Phosphorus; Pressure

How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Creatine Kinase; Creatinine; Drug Resistance, Neoplasm; Energy Metabolism; Energy Transfer; Female; Gene Knockdown Techniques; Humans; Lapatinib; Mice; Mice, Nude; Mitochondria; Mitochondrial Proteins; Phosphocreatine; Phosphorylation; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

(1)H MRS, (31)P MRS and diffusion-weighted MRI (DW-MRI) were applied to study the metabolic changes associated with estrogen dependence in estrogen receptor (ER)-positive BT-474 and triple-negative HCC1806 breast cancer xenografts supplemented with or without 17β-estradiol (E2) at a dose of 0.18 or 0.72 mg/pellet. Furthermore, the effect of estrogen withdrawal on the metabolism of BT-474 and HCC1806 breast cancer xenografts was studied on day 0, day 2 and day 10. Increasing the dose of E2 resulted in a rapid growth and increases in the lactate level and phosphomonoester/β-nucleoside triphosphate (PME/βNTP), phosphocreatine/inorganic phosphate (PCr/Pi) and βNTP/Pi ratios in BT-474 breast cancer xenografts; however, no significant changes were found in HCC1806 breast cancer xenografts. Estrogen withdrawal resulted in a marked decrease in lactate level and PME/βNTP ratio and an observed increase in βNTP/Pi, PCr/Pi and apparent diffusion coefficient (ADC) values of BT-474 breast cancer xenografts on day 10. These data suggest that the lactate level and PME/βNTP, PCr/Pi and βNTP/Pi ratios of ER-positive tumors are closely related to ER dependence.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogens; Female; Humans; Lactic Acid; Magnetic Resonance Spectroscopy; Mice; Neoplasm Transplantation; Phosphates; Phosphocreatine; Transplantation, Heterologous

Persistent cancer-related fatigue (PCRF) is one of the most troubling side-effects of breast cancer (BC) treatment. One explanatory model for PCRF is sickness behavior, which is a set of adaptive responses including sleepiness and depressed mood in reaction to an inflammatory trigger. Prior research has investigated differences in inflammatory cytokines between fatigued and non-fatigued BC survivors, but no study has examined differences in brain metabolites. Differences in inflammatory markers, and brain metabolites using proton magnetic resonance spectroscopy were evaluated within 16 fatigued and 13 non-fatigued BC survivors. Fatigued BC survivors had significantly higher ratios of two markers derived from brain metabolites; namely (a) creatine, normalized to total creatine (creatine + phosphocreatine (Cr/tCr)) ratio (P = 0.03) and (b) glutamate + glutamine (Glx) to N-acetyl-aspartate (NAA) ratio (P = 0.01) in the posterior insula compared to non-fatigued breast cancer survivor. Further, serum IL-6 was increased in fatigued women compared to non-fatigued women (P = 0.03), Using receiver operator curves (ROC) we determined that the posterior insula Glx/NAA ratio was the best predictor of fatigue with an overall area under the receiver operating characteristic curve (AUROC) of 79%, with a sensitivity of 81% and a specificity of 69%. However, posterior insula Glx/NAA, Cr/tCr and serum IL-6 were not significantly correlated with one another implying the possibility of independent biological mechanisms for PCRF rather than an interrelated mechanism as represented by the sickness behavior model. This study provides novel preliminary evidence of several distinct neurobiological changes in the posterior insula associated with PCRF in BC survivors. Future, longitudinal studies are needed to explore these distinct biological phenomena where changes through time in peripheral immune markers and brain metabolites are examined to determine if they correlate with changes in fatigue.

Topics: Aspartic Acid; Biomarkers; Brain; Breast Neoplasms; Creatine; Cross-Sectional Studies; Fatigue; Female; Glutamic Acid; Glutamine; Humans; Interleukin-6; Middle Aged; Phosphocreatine; Pilot Projects; Prognosis; Proton Magnetic Resonance Spectroscopy; Sensitivity and Specificity; Severity of Illness Index; Survivors

Topics: Biopsy, Needle; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Choline; Creatine; Female; Humans; Lymph Nodes; Lymphatic Metastasis; Lysine; Magnetic Resonance Spectroscopy; Mammography; Phosphocreatine

The brain isoform of creatine kinase has been implicated in cellular transformation processes. Cyclocreatine, a creatine kinase substrate analog, was previously shown to be cytotoxic to a broad spectrum of solid tumors. We have synthesized, enzymatically characterized, and evaluated the antitumor activity of a series of substrate analogs of creatine kinase. Using in vitro assays, we demonstrate that several of these analogs are cytotoxic to the human ME-180 cervical carcinoma, the MCF-7 breast adenocarcinoma and the HT-29 colon adenocarcinoma cell lines at low mM concentrations. Analogs that were active in vitro delayed the growth of a subcutaneously implanted rat 13,762 mammary adenocarcinoma. Tumor growth delays of 6-8 days were achieved, which is comparable to effects seen with standard regimens of currently used anticancer drugs. These studies further establish the creatine kinase system as a promising and novel target for anticancer chemotherapy drug design.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Death; Colonic Neoplasms; Creatine; Creatine Kinase; Creatinine; Female; Humans; Neoplasms, Experimental; Phosphocreatine; Rats; Tumor Cells, Cultured; Uterine Cervical Neoplasms

The effect of estrogen withdrawal on energy metabolism was studied in four human breast cancer xenografts: the estrogen-dependent MCF-7 and ZR75-1 and the estrogen-independent ZR75/LCC-3 and MDA-MB-231. The tumors were grown in ovariectomized nude mice with a s.c. implanted estrogen pellet. After Gompertzian growth was verified, the estrogen pellet was removed from half of the animals. In vivo 31P magnetic resonance spectroscopy of the tumors was performed 1 day before and on days 2, 6, and 14 after estrogen removal. Estrogen withdrawal induced a significant increase in the nucleoside triphosphate:Pi ratio in the two estrogen-dependent xenografts, whereas this ratio remained unchanged in the estrogen-independent tumors. In ZR75/LCC-3 tumors a slight decrease in nucleoside triphosphate:Pi was observed following onset of estrogen stimulation after initial growth without estrogen. Extracts of freeze-clamped tumors prepared 14 days after estrogen removal were analyzed for ATP and phosphocreatine content. Our findings suggest a correlation between estrogen withdrawal and the steady-state concentrations of ATP, phosphocreatine, and Pi in human breast cancer xenografts. Discrimination analysis of the pretherapeutic spectra enabled us to identify the tumor line and the estrogen dependence of the tumors in 80-90% of all cases.

Topics: Animals; Breast Neoplasms; Cell Division; Cell Line; Drug Implants; Energy Metabolism; Estradiol; Female; Humans; Kinetics; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Ovariectomy; Phosphates; Phosphocreatine; Phosphorus; Ribonucleotides; Transplantation, Heterologous; Tumor Cells, Cultured

We have studied the metabolism of 31P-containing metabolites of post-menopausal breast cancers in vivo using magnetic resonance spectroscopy (MRS) and a 5.5 cm surface coil. Spectra were acquired from 23 diameter. The spectra of the 19 previously untreated tumours had significantly higher phosphomonoester (PME) 31P relative peak areas than the normal breasts of eight post-menopausal women (11.7% and 7.7% respectively, P = 0.002). Although an increased PME relative peak area was characteristic of malignancy, PME relative peak area is similarly raised in lactating breast and, therefore, not a specific feature of cancer. An apparently lower nucleotide triphosphate (NTP) relative peak area in tumours than healthy postmenopausal breast was secondary to the differences in PME relative peak area; contamination by signal from chest wall muscle probably accounts for the ostensibly higher phosphocreatine (PCr) relative peak area of the tumours. Spectroscopy was repeated following chemotherapy in six women. An increase in PCr relative peak area was seen in all five patients who responded, but again this may represent increased contamination secondary to changes in tumour size. A fall in PME relative peak area was noted in four responders, but also one non-responder, so this finding may not be sufficiently specific to be of use clinically. Further studies are need to elucidate fully the role of MRS in breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Epirubicin; Female; Fluorouracil; Humans; Magnetic Resonance Spectroscopy; Methotrexate; Middle Aged; Phosphates; Phosphocreatine; Phosphorus; Postmenopause; Reference Values; Ribonucleotides

Using image-guided volume-selection techniques, in vivo phosphorus-31 magnetic resonance (MR) spectroscopic profiles were obtained from 12 patients with malignant breast tumors, six patients with benign breast tumors, and nine volunteers with no underlying pathologic condition. Phosphatic metabolites identified in the spectral profiles included the phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphorylated glycans (PG), phosphocreatine (PCr) and adenosine triphosphate (ATP). Based on the results of previous high-resolution ex vivo 31P MR spectroscopic analyses of breast tissues, the resonance of PG was identified in malignant and benign breast tumors. Malignant tumors were found to have a significantly (P less than .05) lower concentration of (PME + Pi) than normal breast parenchyma, and were distinguishable from both benign tumors and normal breast parenchymal tissue by significantly (P less than .01) elevated levels of (PDE + PG). 31P MR spectroscopy is the first technique potentially capable of differentiating among malignant breast tumors, benign breast tumors, and normal breast parenchymal tissues based on their in vivo phosphatic metabolic profiles.

Topics: Adenosine Triphosphate; Adult; Aged; Breast Diseases; Breast Neoplasms; Female; Humans; Magnetic Resonance Spectroscopy; Middle Aged; Phosphates; Phosphocreatine

Serum levels of total sialic acid, carcinoembryonic antigen (CEA), ferritin, lactate dehydrogenase, and creatine phosphokinase were measured both in tumor drainage blood (axillary vein) and in peripheral blood obtained from 121 breast cancer patients during surgery. No significant differences between mean values in peripheral and tumor draining blood, between cancer patients and healthy controls, or between patients with or without axillary lymph node metastases were found for any of the markers. Both ferritin and CEA levels were higher in axillary and peripheral blood from patients with central breast cancer versus other sites but the difference was significant only for CEA (p less than 0.05). CEA levels were significantly higher (p less than 0.01) in patients with greater than 2 cm diameter carcinomas versus T1 stage patients in axillary but not in peripheral blood. When the cephalic vein was clamped before the axillary sample was taken, ferritin showed a significant increase (p less than 0.05). We conclude that measurement of sialic acid, CEA, and ferritin in axillary venous blood in breast cancer patients is not of clinical benefit, although further data are needed to clarify whether other advantages can be derived.

Topics: Adult; Aged; Axillary Vein; Biomarkers, Tumor; Blood Proteins; Breast Neoplasms; Carcinoembryonic Antigen; Drainage; Elbow; Ferritins; Humans; L-Lactate Dehydrogenase; Middle Aged; Phosphocreatine; Sialic Acids; Veins

The concentration of phosphates and the kinetics of phosphate transfer reactions were measured in the human breast cancer cell line, T47D, using 31P-NMR spectroscopy. The cells were embedded in agarose filaments and perifused with oxygenated medium during the NMR measurements. The following phosphates were identified in spectra of perifused cells and of cell extracts: phosphorylcholine (PC), phosphorylethanolamine (PE), the glycerol derivatives of PC and PE, inorganic phosphate (Pi), phosphocreatine (PCr), nucleoside triphosphate (primarily ATP) and uridine diphosphate glucose. The rates of the transfers: PC----gamma ATP (0.2 mM/s), Pi----gamma ATP (0.2 mM/s) and the conversion beta ATP----beta ADP (1.3 mM/s) were determined from analysis of data obtained in steady-state saturation transfer and inversion recovery experiments. Data from spectrophotometric assays of the specific activity of creatine kinase (approx. 0.1 mumol/min per mg protein) and adenylate kinase (approx. 0.4 mumol/min per mg protein) suggest that the beta ATP----beta ADP rate is dominated by the latter reaction. The ratio between the rate of ATP synthesis from Pi and the rate of consumption of oxygen atoms (4 X 10(-3) mM/s) was approx. 50. This high value and preliminary measurements of the rate of lactate production from glucose, indicated that aerobic glycolysis is the main pathway of ATP synthesis.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adenylyl Cyclases; Breast Neoplasms; Cell Line; Creatine Kinase; Female; Humans; Kinetics; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine

Topics: Adenosine Triphosphate; Animals; Breast Neoplasms; Cell Line; Colonic Neoplasms; Female; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Magnetic Resonance Spectroscopy; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Phosphates; Phosphocreatine; Transplantation, Heterologous