Biological activity of antitumoural MGBG: the structural variable

Marques, M. P. M.; Gil, Francisco; Calheiros, Rita; Battaglia, Valentina; Brunati, Anna Maria; Agostinelli, Enzo; Toninello, Antonio

doi:10.1007/s00726-007-0009-2

Cited by 8 publications

(7 citation statements)

References 52 publications

(47 reference statements)

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“…However, subsequent clinical investigations have shown that particular administration conditions strongly reduce MGBG's toxicity while preserving its antitumoural action (Von Hoff 1994). In order to establish the relationship between MGBG's structural preferences and its biological action-in particular, its transport mechanism(s), binding to macromolecular structures and MPT prevention-a conformational analysis in aqueous solution, as a function of pH, was carried out through theoretical methods (Marques et al 2008). A complete geometry optimisation was carried out, considering the molecule's different protonation states, with particular emphasis on the diprotonated form, which is the major species under physiological conditions (pK (MGBG) = 7.5 and 9.2).…”

Section: Biological Function Of Anticancer Methylglyoxal Bis(guanylhymentioning

confidence: 99%

Polyamines: fundamental characters in chemistry and biology

et al. 2009

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Polyamines are small cationic molecules required for cellular proliferation and are detected at higher concentrations in most tumour tissues, compared to normal tissues. Agmatine (AGM), a biogenic amine, is able to arrest proliferation in cell lines by depleting intracellular polyamine levels. It enters mammalian cells via the polyamine transport system. Agmatine is able to induce oxidative stress in mitochondria at low concentrations (10 or 100 lM), while at higher concentrations (e.g. 1-2 mM) it does not affect mitochondrial respiration and is ineffective in inducing any oxidative stress. As this effect is strictly correlated with the mitochondrial permeability transition induction and the triggering of the pro-apoptotic pathway, AGM may be considered as a regulator of this type of cell death. Furthermore, polyamine transport is positively correlated with the rate of cellular proliferation. By increasing the expression of antizyme, a protein that inhibits polyamine biosynthesis and transport, AGM also exhibits a regulatory effect on cell proliferation. Methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase, displaying anticancer activity, is a structural analogue of the natural polyamine spermidine. MGBG has been extensively studied, preclinically as well as clinically, and its anticancer activity has been attributed to the inhibition of polyamine biosynthesis and also to its effect on mitochondrial function. Numerous findings have suggested that MGBG might be used as a chemotherapeutic agent against cancer.

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Section: Biological Function Of Anticancer Methylglyoxal Bis(guanylhymentioning

confidence: 99%

Polyamines: fundamental characters in chemistry and biology

et al. 2009

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“…The data are expressed as a percentage of the control MTT reduction (100%), and represent the average±SD from one independent experiments carried out in duplicate (*p < 0.05; **p < 0.001 and # p < 0.0001). cultures of rat hepatocytes [20] as well as on a reported study on human histiocytic lymphoma that evidenced a decrease in protein synthesis after 20 to 25 h of exposure to the compound [21]. MGBG´s antiproliferative activity is suggested to be delayed due to conformational rearrangements undergone by the molecule at physiological conditions (since several species, with distinct activities, may coexist in the plasma).…”

Section: Resultsmentioning

confidence: 99%

“…MGBG´s cellular uptake is proposed to occur through the transport system of biogenic polyamines [20]. By inhibiting S-adenosylmethionine decarboxylase, it leads to a decrease of the spermidine and spermine intracellular concentration, consequently reducing in vitro cell growth and viability.…”

Section: Resultsmentioning

confidence: 99%

MGBG in Combined Anticancer Chemotherapy

Gonçalves¹,

Kriechammer²,

Marques³

2011

LDDD

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Abstract:The combined activity of MGBG (metylglyoxal-bis(guanylhydrazone)) with either cisplatin or carboplatin was investigated, towards the human breast cancer cell line MCF-7. While a dose-and time-dependent cytotoxic activity was already observed for MGBG alone, a synergistic and non-reversible effect was verified upon co-administration with these Pt-based drugs. Furthermore, toxicity against non-neoplastic cells was shown to be quite low for these drug cocktails, as opposed to either Pt-agents alone. These results may hopefully allow to use lower dosages of both MGBG and the Ptdrugs, minimising the drug´s deleterious side effects while keeping antitumour efficacy, in an anticancer strategy that couples interference with polyamine homeostasis with DNA damage.

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“…MGBG is another compound, which directly activates the mitochondrial pathway. MGBG produces reactive oxygen species, interacts with the polyamine metabolism and thereby impairs the mitochondrial function [137].…”

Section: Conventional Oncologic Therapiesmentioning

confidence: 99%

Apoptotic Signaling in Pancreatic Cancer – Therapeutic Application (Supplemental Data)

Rückert¹,

Pilarsky²,

Saeger³

et al. 2009

CCTR

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Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to the higher resistance of pancreatic tumor cells to oncologic treatment. PDAC cells have accumulated different molecular mechanisms, which enable survival against cytotoxic therapies. Defects of the apoptosis pathway play a crucial role.For the last 10 years, many investigations were underway to get insights into the details of the anti-apoptotic mechanisms of PDAC cells. The present review provides a comprehensive description of the molecular signaling of the apoptotic pathway, an incentive on the potential pathogenetic role of different molecular defects on existing oncologic treatments and an appraisal of the most recent therapeutic strategies applied at a cell biochemical level.

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Biological activity of antitumoural MGBG: the structural variable

Cited by 8 publications

References 52 publications

Polyamines: fundamental characters in chemistry and biology

Polyamines: fundamental characters in chemistry and biology

MGBG in Combined Anticancer Chemotherapy

Apoptotic Signaling in Pancreatic Cancer – Therapeutic Application (Supplemental Data)

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