Ameliorative effect of riboflavin on the cisplatin induced nephrotoxicity and hepatotoxicity under photoillumination
Introduction
Cisplatin (cis-diamminedichloroplatinum II, CIS) is platinum coordinated complex based anticancer drug used against many human cancers including oral, lung, head and neck cancer, metastatic tumors of testis and ovaries, advanced bladder cancer and many other solid tumors (Gottfried et al., 2008, Turk et al., 2008). In spite of its effective anticancer behavior, it exerts many unwanted side effects including nephrotoxicity, hepatotoxicity, ototoxicity, emetogenesis myelosuppression and spermiotoxicity (Tarladacalisir et al., 2008, Liao et al., 2008, Atessahin et al., 2006, Mc Keage, 1995). Hence, these major side effects limit the clinical use of the drug.
The anticancer property of CIS comes from its ability to bind to N-7 of purine bases of cellular DNA leading to formation of mono-adducts which are later transformed into inter- and intra-strand cross links by reaction of second reactive site of the drug with the second nucleobase (Hah et al., 2006, Fichtinger-Schepman et al., 1985). This is inhibitory to fundamental cellular processes including replication, transcription, translation and DNA-repair in many cell types (Suo et al., 1999). Beside these, CIS generates oxidative and nitrosative stresses (Srivastava et al., 1996, Xiao et al., 2003) because of depletion or inhibition of antioxidant enzymes and proteins which results into nephrotoxicity and hepatotoxicity as major side effects of the drug (Iseri et al., 2007, Naziroglu et al., 2004).
Riboflavin (RF) or vitamin B2 is chemically 6,7-dimethyl-9-d-1-ribityl isoalloxazine. It is a natural constituent of all forms of life, exists in the two co-enzymatic forms – flavinadenine dinucleotide (FAD) and flavinadenine mononucleotide (FMN) that are used in metabolic redox reaction by different enzyme-systems. It also acts as photosensitizer via radical species or via the generation of singlet oxygen. It reacts via its singlet and triplet excited states with molecular oxygen leading to generation of superoxide anion, riboflavin radical (Kumari et al., 1996) and generates hydroxyl radical in presence of transition metal ions (Yoshida et al., 2003). These species exert a collective damaging effect on several biologically important molecules (Jazzer and Naseem, 1994, Jazzer and Naseem, 1996) and can also affect the drugs as well as the medicines (Cosa, 2004). Apart from being an essential vitamin, its photosensitizing property makes it an effective agent for photodynamic therapy in killing tumors (Edwards et al., 1994), inactivation of neurotoxin A (Eubanks et al., 2005), treatment of neonatal hyperbilirubinemia, blue nevi, pigmented skin lesions (Sato et al., 2000) and sterilization of blood products (Cui et al., 2008). The present study was designed to enlarge the therapeutic window of RF to regulate the nephrotoxic and hepatotoxic effects of CIS in mice as animal model system. It is a preliminary attempt to suggest alternative regime for the cancer patients undergoing CIS based chemotherapy based on our earlier in vitro observation.
Section snippets
Chemicals
Riboflavin, cisplatin, reduced and oxidized glutathione, nicotinamide adenine dinucleotide phosphate reduced (NADPH), nicotinamide adenine dinucleotide reduced (NADH) were bought from Sigma–Aldrich Chemical Company, USA. Succinic acid, potassium dihydrogen and monohydrogen phosphate, glycine, pyrogallol, hydrogen peroxide, trichloroacetic acid (TCA) and ethylenediaminetetra-acetic acid (EDTA) were purchased from Qualigens Fine Chemicals, Mumbai, India. Folin’s phenol reagent, bovine serum
Results
The animals were given 8 intraperitoneal doses of the treatment. They were sacrificed all together on the same day. Major target organs of the treatment – kidney and liver and the blood of all mice were collected. Their organs were homogenized and blood was centrifuged to get the supernatants and the serums, respectively, at −4 °C and was stored at −20 °C after that. Their biochemical study and analysis were carried-out to see whether the groups fifth and sixth showed any recovery or healing from
Discussion
Cisplatin (CIS) is one of the most widely used anticancer drug for the treatment of various cancers and solid tumors (Sweetman, 2002). However, its major side effects – nephrotoxicity and hepatotoxicity are the main limiting factors of its clinical use for long term treatment (Antunes et al., 2000, Zicca et al., 2002). Various treatment-strategies and curing agents have been tried and used to monitor or control its side effects since its discovery. Earlier studies from our lab have shown that
Conclusion
It may be hypothesized that the excitable electrons in alloxazine ring of RF may interact with the active groups of CIS at the molecular level which may possibly lead to decreased production of ROS by CIS thereby reducing the oxidative stress as well as suppressing the riboflavin prooxidant potential leading to decreased ROS generation in the target organs and correspondingly improved status of the organs effected by CIS toxicity. Hence, our work opens a novel window to manage CIS-induced
Conflict of Interest
The authors declare that there are no conflicts of interest.
Acknowledgements
The authors acknowledge the financial assistance provided by the University Grant Commission (UGC), New Delhi under SAP program, DST-FIST and the facilities provided by the Department of Biochemistry, Aligarh Muslim University. We are also thankful to Prof. Riyaz Mahmood, Dr. Shams Tabrez, all the friends, lab colleagues and the fellows who directly or indirectly helped us during different phases of treatment and experimentation in this work.
References (44)
Catalase in vitro
Meth. Enzymol.
(1984)- et al.
Glutathione reductase
Meth. Enzymol.
(1985) - et al.
A possible anti-proliferative and anti-metastatic effect of irradiated riboflavin in solid tumors
Cancer Lett.
(2007) - et al.
Visible light effects on tumoral cells in a culture medium enriched with tryptophan and riboflavin
J. Photochem. Photobiol. B: Biol.
(1994) - et al.
Vitamin B2-mediated cellular photoinhibition of botulinum neurotoxin A
FEBS Lett.
(2005) - et al.
Cisplatin-based three drugs combination (NIP) as induction and adjuvant treatment in locally advanced non-small cell lung cancer: final results
J. Thorac. Oncol.
(2008) - et al.
Glutathione S-transferase: the first enzymatic step in mercapturic acid formation
J. Biol. Chem.
(1974) - et al.
γ-Glutamyl transpeptidase deficient mice are resistant to the nephrotoxic effects of cisplatin
Am. J. Pathol.
(2001) - et al.
Simvastatin attenuates cisplatin-induced kidney and liver damage in rats
Toxicology
(2007) - et al.
Carbonyl assay for determination of oxidatively modified proteins
Meth. Enzymol.
(1994)