Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.

Antitumor Effect of Zwitterions of Imidazolium Derived from L-methionine in BALB/c Mice with Lymphoma L5178Y

Background: In the therapy of cancer, several treatments have been designed using nanomaterials, among which gold nanoparticles (AuNPs) have been featured as a promising antitumoral agent. Our research group has developed the synthesis of gold nanoparticles L-AuNPs and D-AuNPs stabilized with zwitterions of imidazolium (L-1 and D-1) derived from L-methionine and D-methionine. Because the stabilizer agent is chiral, we observed through circular dichroism that AuNPs also present chirality; such chirality as well as the fact that the stabilizing agent contains fragments of methionine and imidazolium that are commonly involved in biological processes, opens up the possibility that this system may have biological compatibility. Additionally, the presence of methionine in the stabilizing agent opens the application of this system as a possible antitumor agent because methionine is involved in methylation processes of molecules such as DNA. Objective: The aim of this research is the evaluation of the antitumor activity of gold nanoparticles stabilized with zwitterions of imidazolium (L-AuNPs) derived from L-methionine in the model of BALB/c mice with lymphoma L5178Y. Methods: Taking as a parameter cell density, the evaluation of the inhibitory effect of L-AuNPs was carried out with a series of in vivo tests in BALB/c type mice; three groups of five mice each were formed (Groups 1, 2 and 3); all mice were i.p. inoculated with the lymphoblast murine L5178Y. Group 1 consisted of mice without treatment. In the Groups 2 and 3 the mice were treated with L-AuNPs at 0.3 mg/Kg on days 1, 7 and 14 by orally and intraperitonally respectively. Results: These results show low antitumor activity of these gold nanoparticles (L-NPsAu) but interestingly, the imidazolium stabilizing agent of gold nanoparticle (L-1) displayed promising antitumor activity. On the other hand, the enantiomer of L-1, (D-1) as well as asymmetric imidazole derivate from L-methionine (L-2), do not exhibit the same activity as L-1. Conclusion: The imidazolium stabilizing agent (L-1) displayed promising antitumor activity. Modifications in the structure of L-1 showed that, the stereochemistry (like D-1) and the presence of methionine fragments (like L-2) are determinants in the antitumor activity of this compound.

Decitabine bioproduction using a biocatalyst with improved stability by adding nanocomposites

A novel IDA-LaNDT derivative was able to reach the highest productivity in the biosynthesis of a well-known antitumoral agent called decitabine. However, the combination of two simple and inexpensive techniques such as ionic absorption and gel entrapment with the incorporation of a bionanocomposite such as bentonite significantly improved the stability of this biocatalyst. These modifications allowed the enhancement of storage stability (for at least 18 months), reusability (400 h of successive batches without significant loss of its initial activity), and thermal and solvent stability with respect to the non-entrapped derivative. Moreover, reaction conditions were optimized by increasing the solubility of 5-aza by dilution with dimethylsulfoxide. Therefore, a scale-up of the bioprocess was assayed using the developed biocatalyst, obtaining 221 mg/L·h of DAC. Finally, green parameters were calculated using the nanostabilized biocatalyst, whose results indicated that it was able to biosynthesize DAC by a smooth, cheap, and environmentally friendly methodology.

Decitabine bioproduction using a biocatalyst with improved stability by adding nanocomposites

A novel IDA-LaNDT derivative was able to reach the highest productivity in the biosynthesis of a well-known antitumoral agent called decitabine. However, the combination of two simple and inexpensive techniques such as ionic absorption and gel entrapment with the incorporation of a bionanocomposite such as bentonite significantly improved the stability of this biocatalyst. These modifications allowed the enhancement of storage stability (for at least 18 months), reusability (400 h of successive batches without significant loss of its initial activity), and thermal and solvent stability with respect to the non-entrapped derivative. Moreover, reaction conditions were optimized by increasing the solubility of 5-aza by dilution with dimethylsulfoxide. Therefore, a scale-up of the bioprocess was assayed using the developed biocatalyst, obtaining 221 mg/L.h of DAC. Finally, green parameters were calculated using the nanostabilized biocatalyst, whose results indicated that it was able to biosynthesize DAC by a smooth, cheap, and environmentally friendly methodology.

Pharmacokinetic parameters of ifosfamide in mouse pre-administered with grapefruit juice or naringin

Grapefruit juice (GFJ) and naringin when consumed previously or together with medications may alter their bioavailavility and consequently the clinical effect. Ifosfamide (IF) is an antitumoral agent prescribed against various types of cancer. Nevertheless, there is no information regarding its interaction with the ingestion of GFJ or naringin. The aims of the present report were validating a method for the quantitation of IF in the plasma of mouse, and determine if mice pretreated with GFJ or naringin may modify the IF pharmacokinetics. Our HPLC results to quantify IF showed adequate intra and inter-day precision (RSD < 15%) and accuracy (RE < 15%) indicating reliability. Also, the administration of GFJ or naringin increased Cmax of IF 22.9% and 17.8%, respectively, and decreased Tmax of IF 19.2 and 53.8%, respectively. The concentration of IF was higher when GFJ (71.35 ± 3.5 µg/mL) was administered with respect to that obtained in the combination naringin with IF (64.12 ± µg/mL); however, the time required to reach such concentration was significantly lower when naringin was administered (p < 0.5). We concluded that pre-administering GFJ and naringin to mice increased the Tmax and decreased the Cmax of IF.

HISTORIA NATURAL DE LA ESPONJA DISCODERMIA DISSOLUTA (PORIFERA: DEMOSPONGIAE: LITHISTIDA) EN SANTA MARTA, CARIBE COLOMBIANO

The marine sponge Discodermia dissoluta is a source of the polyketide discodermolide, a potent antitumoral agent that has reached clinical trials in humans. In Santa Marta, where this species occurs at shallower depths than in other Caribbean areas, for the first time it was possible to study by SCUBA its ecological characteristics, distribution and abundance. By searching the base of the reefs (12-25 m in depth) it was found that this species is restricted to sites or bays with relatively low wave-exposure, dwelling predominantly in hard, horizontal to inclined substrata, generally exposed to light. Censuses carried out in 4 m-radius circles in sectors where this sponge occurs showed moderate densities (about 2-5 ind/50 m2) that, although not very low, do not support its commercial exploitation to obtain discodermolide. By locating individuals in the sampling space and using the point pattern distribution functions F, G and K, it was determined that individuals of D. dissoluta are aggregated in patches at scales from decimeters to a few meters. This pattern possibly arises from short-distance larval dispersal or fragmentation, both common in sponges. Size of censused individuals was estimated as projected area from digital photos, and expressed in volume by a regression calculated from the real volume of 30 collected individuals. In the population, small individuals (<50 mL) predominate, while several very large ones (reaching 2000 mL) persist, indicating high mortality in small and medium sizes. This population is viable for individual marking and follow-up studies and application of in situ and biotechnological cultures techniques in order to develop sustainable methods for production and supply of discodermolide.

Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells

Recent epidemiological studies indicate that the antidiabetic drug metformin has chemosensitizing and chemopreventive effects against carcinogenesis. Here, we demonstrate that metformin exerts varying degrees of antitumor activity against human leukemia cells, as reflected by differences in growth inhibition, apoptosis, and alterations to metabolic enzymes. In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis. In all sensitive cells, metformin decreased the Δψm and it modified the expression of enzymes involved in energy metabolism: PKCε (PKCepsilon) and PKCδ (PKCdelta). In sensitive cells, metformin altered PKCε and PKCδ expression leading to a predominance of PKCε over PKCδ which implies a more glycolytic state. The opposite occurs in the nonresponsive cells. In conclusion, we provide new insights into the activity of metformin as an antitumoral agent in leukemia cells that could be related to its capability to modulate energy metabolism.