Gold Complexes As Potential Therapeutic Agent Against Tumor Cells #biopharma #medtech
The treatment of a various cancers types by platinum derivatives has encouraged the further investigation of alternative drugs which are metal-based. Some gold (I) compounds that were used for the treatment of rheumatoid arthritis were considered for possible anticancer activity because of their anti-inflammatory and immunosuppressive properties.
Due to poor stability of gold (III) under physiological conditions, its development as antitumor agent has been hampered till now. The stability of gold (III) metal center may be increased by the coordination of multi dentate ligands with it, on the other hand, excess stabilization may results in a loss of biological activity. However, recent researches showed that some selected gold (III) complexes are able to show cytotoxic activity toward many tumor cell lines.
Platinum and gold, both are involved to target the DNA within nucleus. Nevertheless, gold (I) and gold (III) interact with other cellular components as well. A recent study has shown that complexes of gold (III)-methylsarcosinedithiocarbamato derivatives have apoptotic and anti proliferative activity towards cancer cells. They are reported to inhibit the anti apoptotic Bcl-2 molecules and up regulate the Bax molecules which are pro apoptotic. Furthermore, it was identified that gold dithiocarbamato derivatives also target the proteosomes. This results in accumulation of ubiquitinous proteins.
The complexes were designed to very closely reproduce the features of cis-platin (reference drug). Many spectroscopic techniques suggest that both DMDT (DMDT = N,N-dimethyldithiocarbamate) and ESDT (ethylsarcosinedithiocarbamato) ligands occur in square planer geometry through sulfur donating atoms and the NCSS moiety coordinates with metal centre via bidentate symmetrical mode. The remaining positions are covered by two cis-gold (III) and halogen atoms. This whole information is recently confirmed by X-Ray crystallography.
The apoptotic activity of the complexes was observed on human cervical carcinoma HeLa cells for 24 hours after incubation with increasing drug concentration. Cis-platin was tested as reference drug. Results indicated that both DMDT and ESDT were able to induce apoptosis in a dose dependant fashion. Poly-(ADP-ribose)-polymerase (PARP) cleavage was analyzed as a marker of apoptosis. The percentage of PARP cleavage was determined after 24 hours through densitometric analysis which indicated the same results for all the gold complexes tested and was non-dose dependant. Surprisingly the results were against the morphological examination which was dose-dependent. The results confirmed that designed drug induces cell death not only via apoptosis but other pathways too like necrosis.
EFFECTS ON MITOCHONDRIAL FUNCTIONS:
Mitochondrial respiratory parameters, permeability transition and membrane potential were determined after treatment with complexes. Respiratory control ratio (RCR) is hardly affected for all the complexes indicating that electron flow through respiratory chain is not affected significantly.
Determination of membrane potential was surprisingly different for different complexes. Complex I and II caused a decrease in membrane potential after 20 to 30 mins of incubation whereas, complex IV depolarized the membrane after 32 mins of incubation. Complex III had an intermediate behavior.
MOLECULAR TARGETS AT CYTOSOLIC AND MITOCHONDRIAL LEVEL:
Thioredoxin reductase is considered as potential target on of antitumor agents. Studies indicated that gold I and III complexes are very specific inhibitors of this mitochondrial enzyme. On the basis of this knowledge gold III-dithiocarbamato derivatives were checked for their affects on cytosolic and mitochondrial thioredoxin reductase. Results indicated that cytosolic thioredoxin reductase is more sensitive towards gold III complex as compared to mitochondrial enzyme. Nevertheless, the inhibitory affect is massive in both cases. Glutathione reductase is totally insensitive towards complexes because it does not contain selenol group at its catalytic site which is actual target of the complexes in thioredoxin reductase.
SIGNIFICANCE OF GOLD PARTICLES:
Gold particles have various therapeutic applications including suppression of autoimmunity, antitumor activity as well as attenuation of inflammation. Structural similarity of gold with platinum indicated their targeting of DNA. However, Gold III also interacts with other cellular components. But the mechanism of action of gold particles is still unclear to some extent. The action of Gold-III-dithiocarbamato derivatives has been analyzed through cellular molecular and biochemical approaches. They trigger cell death via impairment of TrxR, induce ROS generation, and inhibit both cytosolic and mitochondrial thioredoxin reductase.