Sandesh Chibber

Ameliorative effect of riboflavin on the cisplatin induced nephrotoxicity and hepatotoxicity under photoillumination.

Cisplatin is a widely used anticancer drug. It is documented that it elicits major side effects like nephrotoxicity and hepatotoxicity due to oxidative stress forcing the patients to limit its clinical use in long term treatment. Riboflavin (vitamin B(2)) is a strong photosensitizer because it generates reactive oxygen species (ROS) upon photoillumination. We have tried to trap its photosensitizing property to ameliorate the cisplatin induced nephrotoxicity and hepatotoxicity in mice. They were treated with riboflavin and cisplatin separately as well as with their combination under photoilluminated condition. The status of major antioxidant enzymes, antioxidant proteins, functional markers, lipid peroxidation and protein oxidation was studied in liver, kidneys and serum samples of all the groups. Cisplatin treated group showed significantly compromised level of antioxidant enzymes and the proteins with higher extent of lipid and protein oxidation. Similar but less pronounced pattern was observed in the riboflavin treated group. The groups treated with the combination of cisplatin and riboflavin showed all the parameters tended towards normal levels in a dose dependent manner. Hence, it can be hypothesized that riboflavin shows ameliorative effect on the cisplatin induced nephrotoxicity and hepatotoxicity under the mentioned treatment conditions.

Riboflavin Ameliorates Cisplatin Induced Toxicities under Photoillumination

Background Cisplatin is an effective anticancer drug that elicits many side effects mainly due to induction of oxidative and nitrosative stresses during prolonged chemotherapy. The severity of these side effects consequently restricts its clinical use under long term treatment. Riboflavin is an essential vitamin used in various metabolic redox reactions in the form of flavin adenine dinucleotide and flavin mononucleotide. Besides, it has excellent photosensitizing property that can be used to ameliorate these toxicities in mice under photodynamic therapy. Methods and Findings Riboflavin, cisplatin and their combinations were given to the separate groups of mice under photoilluminated condition under specific treatment regime. Their kidney and liver were excised for comet assay and histopathological studies. Furthermore, Fourier Transform Infrared Spectroscopy of riboflavin-cisplatin combination in vitro was also conducted to investigate any possible interaction between the two compounds. Their comet assay and histopathological examination revealed that riboflavin in combination with cisplatin was able to protect the tissues from cisplatin induced toxicities and damages. Moreover, Fourier Transform Infrared Spectroscopy analysis of the combination indicated a strong molecular interaction among their constituent groups that may be assigned for the protective effect of the combination in the treated animals. Conclusion Inclusion of riboflavin diminishes cisplatin induced toxicities which may possibly make the cisplatin-riboflavin combination, an effective treatment strategy under chemoradiotherapy in pronouncing its antineoplastic activity and sensitivity towards the cancer cells as compared to cisplatin alone.

New vision to CuO, ZnO, and TiO2 nanoparticles: their outcome and effects

Nanomaterials and nanotechnology have attracted more and more attention due to their wide ranges of applications in various fields. With a high level of surface energy, high magnetism, high surface area, and low melting point, engineered nanoparticles (ENPs) has been widely used in industry for various applications. Metal nanoparticles, in particular, have been shown to cause significant biological effects. Review discusses cytotoxic to neurotoxic effects of CuO, ZnO, and TiO2 nanoparticles based on the scenario drawn from various in vitro and in vivo studies. ENPs such as TiO2 and ZnO NPs have great practical importance in industrial applications. CuO NPs is also widely used in biomedical applications as catalyst supports, drug carriers, and gene delivery. However, study conducted on TiO2 NPs have forecast that oxidative DNA damage could be attributed due to reduced glutathione levels with concomitant increase in lipid peroxidation and reactive oxygen species generation. Moreover, there are many evidences showing that ZnO NP and CuO NPs generates ROS production and can cause cell death in different types of cultured cell. Nanoparticle toxicity is assessed by set of tests designed to characterize a given risk and also the mechanism for related outcomes. Conclusively, it becomes more and more important for nanotechnologist to understand the potential health effects of ENPs and what new methodology can be applied to reveal problems like gene silencing and inhibition in antioxidant defense mechanism which can be occurred on severe effects to oxidative stress by ENPs.

White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

Abstract5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N1–C5-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis.

Vitamin B2: A promising adjuvant in cisplatin based chemoradiotherapy by cellular redox management

Cancer has been a big challenge in the clinical research arena for many years. All the major anticancer drugs are either not effective or induce serious side effects. Cisplatin (CP) is one of the most valued anticancer drugs against various forms of cancer but it exerts many side effects often resulting in withdrawal of clinical usage during long-term chemotherapy. Thus, increasing the efficacy of the drugs and minimizing deleterious side effects is needed. Vitamins like riboflavin (RF) are promising under photodynamic therapy in this aspect because of its potential as an efficient adjuvant confirmed in many cancer cell lines and animal-based studies. It has been found to alleviate CP-induced side effects significantly under photoillumination in mice. As CP exerts most of its toxic effects by oxidative and nitrosative stress; clubbing ribophototherapy with chemotherapy involving CP can shift the redox status favoring better cancer treatment. This strategy can not only increase the average life span of the cancer patients but also improve their quality of life significantly. However, cancer is still considered as a disease of genetic and metabolic disorders; hence, attacking both aspects of the disease can give better results as compared to contemporary treatment modalities.

Cisplatin-induced neurotoxicity in vivo can be alleviated by riboflavin under photoillumination.

Cisplatin (CP)-induced neurotoxicity is one of the major clinical problems in CP-based chemoradiotherapy, leading to its discontinuation depending upon their severity. In the present investigation, the photosensitizing property of riboflavin (RF) has been used to ameliorate the CP-induced neurotoxicity. According to dosing plan, the healthy mice were given RF, CP, and their combinations under photoillumination with their controls without any light exposure. After the treatment, antioxidant enzymes, cellular reductants, glutathione-S-transferase, brain markers, and oxidation products were assessed besides histopathology in their brain samples. These parameters revealed that RF ameliorates CP-induced neurotoxicity in a dose-dependent manner under photoillumination. Hence, inclusion of RF in CP-based chemoradiotherapy can be an effective strategy to counter CP-induced neurotoxicity.

Novel aspect of chemophototherapy in treatment of cancer

The present review deals with the genetic implications of reactive oxygen species (ROS) to enhance horizons of chemophototherapy toward novel approaches for the treatment of various cancers. ROS are species of oxygen which are in a more reactive state than molecular oxygen. ROS play essential roles in vivo such as redox regulation, gene expression, immune response and many other cellular events. ROS generated by anticancer drugs during chemophototherapy may be associated with the activation of signal molecules like PKC, transcription factor NF-kappaB as well as destabilization of mitochondrial membrane inducing the release of apoptosis inducing agents like cytochrome c, resulting in toxicity to cancer cells. Thus, we suggest that anticancer drugs on exposure to light may generate oxidative stress following Fenton-like reaction generating hydroxyl radical. This may get on specific cell cycle receptors which may lead to cell cycle arrest and subsequently cytotoxic death of cancer cells.

In vitro pro-oxidant action of Methotrexate in presence of white light

Methotrexate (MTX) an anti-cancer drug as well as a photosensitizer is able to generate reactive oxygen species (ROS). Cu (II) is present associated with chromatin in cancer cells and has been shown to be capable of mediating the action of several anti-cancer drugs through production of ROS. The objective of the present study is to determine Cu (II) mediated anti-cancer mechanism of MTX under photoilluminated condition as well as alone, using alkaline single cell gel electrophoresis (comet assay). We have shown that cellular DNA breakage was enhanced when Cu (II) is used with MTX as compared to MTX alone. It is also shown that MTX alone as well as in combination with Cu (II) is able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS but the pattern of inhibition was differential as was also demonstrated by plasmid nicking assay. Thus, we can say that MTX exhibit pro-oxidant action in presence of white light which gets elevated in presence of Cu (II). Hence, we propose that the mobilization of endogenous copper is possibly involved in killing of cancer cells by MTX during chemo-radio therapy besides acting as antifolate.

Mobilization of copper ions in human peripheral lymphocytes by catechins leading to oxidative DNA breakage: A structure activity study

Epidemiological studies suggest that dietary consumption of plant polyphenols is related to a lower incidence of various cancers. Among these compounds catechins (present in green tea and other beverages) are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. Thus these compounds can be used as leads to synthesize novel anticancer drugs with greater bioavailability. In view of this in this paper we have examined the chemical basis of cytotoxicity of catechins by studying the structure-activity relationship between catechin (C), epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG). Using single cell alkaline gel electrophoresis (comet assay) we have established the relative efficiency of cellular DNA breakage as EGCG>EGC>EC>C. We also show that cellular DNA breakage is the result of mobilization of copper ions bound to chromatin and the generation of reactive oxygen species. Further the relative DNA binding affinity order was confirmed using molecular docking and thermodynamic studies by studying the interaction of catechins with calf thymus DNA. The results suggest that the synthesis of any novel anti cancer molecule based on the structure of catechins should have as many galloyl moieties as possible resulting in an increased number of hydroxyl groups that may facilitate the binding of the molecule to cellular DNA.

Light-mediated interaction of methotrexate with transition metal Cu(II)

Methotrexate (MTX), an anticancer drug used for treatment of the malignancies is able to generate reactive oxygen species (ROS) upon illumination. Copper has been shown to be capable of mediating the action of several anticancer drugs through production of ROS. Present study is an attempt to characterize the MTX–Cu(II) interaction by spectroscopy. UV–visible and fluorescence spectra shown an enhancement in photoinduced oxidation of MTX when subjected to irradiation with Cu(II) as compared to MTX alone. This may be attributed to the interaction of MTX with Cu(II); which was further confirmed by fourier transform infrared (FTIR) spectroscopy. We have also demonstrated that MTX upon irradiation with white light caused oxidative damage to protein and DNA. This damage to protein and DNA got enhanced in presence of Cu(II). This is probably due to the enhanced generation of hydroxyl radical via Fenton/Haber–Weiss reaction. As Cu(I) is present bound to chromatin thus, when MTX is given as chemotherapeutic agent it possibly could mobilize endogenous Cu(I) and mediate killing of cancer cells through ROS generation.