Creatine and cyclocreatine treatment of human colon adenocarcinoma xenografts: 31P and 1H magnetic resonance spectroscopic studies

Abstract

Summary Creatine (Cr) and cyclocreatine (cyCr) have been shown to inhibit the growth of a variety of human and murine tumours. The purpose of this study was to evaluate the anti-tumour effect of these molecules in relation to drug accumulation, energy metabolism, tumour water accumulation and toxicity. Nude mice carrying a human colon adenocarcinoma (LS174T) with a creatine kinase (CK) activity of 2.12 units mg -1 protein were fed Cr (2.5% or 5%) or cyCr (0.025%, 0.1% or 0.5%) for 2 weeks and compared with controls fed standard diet. Cr concentrations of 2.5% and 5% significantly inhibited tumour growth, as did 0.1% and 0.5% cyCr. In vivo 31 P magnetic resonance spectroscopy (MRS) after 2 weeks of treatment showed an increase in [phosphocreatine (PCr)+phosphocyclocreatine (PcyCr)]/nucleoside triphosphate (NTP) with increasing concentrations of dietary Cr and cyCr, without changes in absolute NTP contents. The antiproliferative effect of the substrates of CK was not related to energy deficiency but was associated with acidosis. Intratumoral substrate concentrations (measured by 1 H-MRS) of 4.8 µmol g -1 wet weight Cr (mice fed 2.5% Cr) and 6.2 µmol g -1 cyCr (mice fed 0.1% cyCr) induced a similar decrease in growth rate, indicating that both substrates were equally potent in tumour growth inhibition. The best correlant of growth inhibition was the total Cr or (cyCr+Cr) concentrations in the tissue. In vivo, these agents did not induce excessive water accumulation and had no systemic effects on the mice (weight loss, hypoglycaemia) that may have caused growth inhibition.

Hodgkin disease‐derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

“…These include a decrease of intracellular pH, 18 inhibition of glycolytic enzymes, 16 stabilization of microtubules, 42 pancreatic hormone levels, 43 inhibition of progression out of all phases of the cell cycle,44 cotransport of Na ϩ followed by an increased intracellular Na ϩ concentration 45 and other unknown downstream effectors. Concerning our experiments, it may be argued that the relatively high cCr concentration (12.5-50 mM) could have a non-specific influence on cell growth, i.e., by increasing the osmolarity of the culture medium.…”

“…15,17 This suggests that trapping of highenergy phosphates in the PcCr pool may lead to an impairment of cellular energy metabolism. cCr treatment does not necessarily alter overall NTP concentrations, however, 16,18 and Cr was shown in mice to have similar inhibitory effects as cCr in solid, transplanted tumors. 18,19 We recently established the cell line L1236 from the peripheral blood of a patient with mixed cellularity HD.…”

“…cCr treatment does not necessarily alter overall NTP concentrations, however, 16,18 and Cr was shown in mice to have similar inhibitory effects as cCr in solid, transplanted tumors. 18,19 We recently established the cell line L1236 from the peripheral blood of a patient with mixed cellularity HD. 20 The L1236 cell line is identical, regarding the rearranged Ig gene sequence, with the Reed-Sternberg cells in the bone marrow of the same patient.…”

“…15,17 This suggests that trapping of highenergy phosphates in the PcCr pool may lead to an impairment of cellular energy metabolism. cCr treatment does not necessarily alter overall NTP concentrations, however, 16,18 and Cr was shown Abbreviations: B-CK, brain cytosolic isoenzyme of …”

Nanofabrication of methylglyoxal with chitosan biopolymer: a potential tool for enhancement of its anticancer effect

“…37,38 Moreover, it is reported in the literature that ascorbic acid augments the anticancer effects of MG. 9 Considering these facts and the beneficial effects of creatine and ascorbic acid, we included them in the treatment regimen along with Nano-MG. In every case of our in vivo treatments, ascorbic acid and creatine acted synergistically with Nano-MG and bare MG in agreement with our previous observation.…”