Limits...
On the discovery, biological effects, and use of Cisplatin and metallocenes in anticancer chemotherapy.

Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluđerović GN - Bioinorg Chem Appl (2012)

Bottom Line: Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed.Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated.Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Spain.

ABSTRACT
The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

No MeSH data available.


Related in: MedlinePlus

Mode of cell death induced by cisplatin: apoptosis (left) and necrosis (right).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3401524&req=5

fig4: Mode of cell death induced by cisplatin: apoptosis (left) and necrosis (right).

Mentions: The net effect of intracellular interaction of cisplatin with DNA and non-DNA targets is the cell cycle arrest and subsequent death in sensitive clones. There are two type of death signals resulting from cellular intoxication by this drug (Figure 4). Fundamentally, the drug concentration presents the critical point for cell decision to undergo apoptotic or necrotic cell death [62]. Primary cultures of proximal tubular cells isolated from mouse died by necrosis if they were exposed to high doses of cisplatin just for a few hours while apoptotic cell death is often triggered by long-term exposure to significantly lower concentrations [63]. However, the presence of necrosis in parallel with apoptosis in tumor-cell population indicated that type of cell death is not just the question of dose but also is defined by cell intrinsic characteristics and energetic status of each cell at the moment of the treatment. In fact, it was considered that intracellular ATP level dictate cell decision to die by necrotic or apoptotic cell death [64, 65]. One of the signals which are provoked with DNA damage is PARP-1 activation and subsequent ATP depletion caused by PARP-1 mediated cleavage of NAD+. This event is a trigger for necrotic cell death. However, activated caspases cleaved the PARP-1, preventing necrotic signal and favor the execution of apoptotic process. On the other hand, the inhibition of caspases by intracellular inhibitors IAP together with continual PARP activity and ATP depletion resulted in necrosis [31]. As numerous biological phenomena, this one is not unidirectional. It was found that failure in PARP cleavage may also serve to apoptosis [66]. This paradox was ascribed to changes in pyridine nucleotide pool as well as in pool of ATP/ADP responsible for regulation of mitochondrial potential [67]. Atypical apoptosis was observed in L1210 leukemia cell line exposed to cisplatin. Different death profiles in cisplatin treated cells confirmed plasticity of signals involved in cell destruction and focus the attention to the molecules responsible for resistance to death as possible targets for the therapy. Having in mind that cisplatin is toxic agent against whom the cell can activate autophagy as protective process; the specific inhibition of autophagy by certain type of molecules could amplify the effectiveness of cisplatin [50].


On the discovery, biological effects, and use of Cisplatin and metallocenes in anticancer chemotherapy.

Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluđerović GN - Bioinorg Chem Appl (2012)

Mode of cell death induced by cisplatin: apoptosis (left) and necrosis (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3401524&req=5

fig4: Mode of cell death induced by cisplatin: apoptosis (left) and necrosis (right).
Mentions: The net effect of intracellular interaction of cisplatin with DNA and non-DNA targets is the cell cycle arrest and subsequent death in sensitive clones. There are two type of death signals resulting from cellular intoxication by this drug (Figure 4). Fundamentally, the drug concentration presents the critical point for cell decision to undergo apoptotic or necrotic cell death [62]. Primary cultures of proximal tubular cells isolated from mouse died by necrosis if they were exposed to high doses of cisplatin just for a few hours while apoptotic cell death is often triggered by long-term exposure to significantly lower concentrations [63]. However, the presence of necrosis in parallel with apoptosis in tumor-cell population indicated that type of cell death is not just the question of dose but also is defined by cell intrinsic characteristics and energetic status of each cell at the moment of the treatment. In fact, it was considered that intracellular ATP level dictate cell decision to die by necrotic or apoptotic cell death [64, 65]. One of the signals which are provoked with DNA damage is PARP-1 activation and subsequent ATP depletion caused by PARP-1 mediated cleavage of NAD+. This event is a trigger for necrotic cell death. However, activated caspases cleaved the PARP-1, preventing necrotic signal and favor the execution of apoptotic process. On the other hand, the inhibition of caspases by intracellular inhibitors IAP together with continual PARP activity and ATP depletion resulted in necrosis [31]. As numerous biological phenomena, this one is not unidirectional. It was found that failure in PARP cleavage may also serve to apoptosis [66]. This paradox was ascribed to changes in pyridine nucleotide pool as well as in pool of ATP/ADP responsible for regulation of mitochondrial potential [67]. Atypical apoptosis was observed in L1210 leukemia cell line exposed to cisplatin. Different death profiles in cisplatin treated cells confirmed plasticity of signals involved in cell destruction and focus the attention to the molecules responsible for resistance to death as possible targets for the therapy. Having in mind that cisplatin is toxic agent against whom the cell can activate autophagy as protective process; the specific inhibition of autophagy by certain type of molecules could amplify the effectiveness of cisplatin [50].

Bottom Line: Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed.Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated.Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Spain.

ABSTRACT
The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

No MeSH data available.


Related in: MedlinePlus