Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.
Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells, selected for resistance to one chemotherapeutic agent, simultaneously acquire resistance to several apparently unrelated drugs. The MDR phenotype is multifactorial. The best-studied mechanism involves the expression of a membrane protein that acts as an energy-dependent efflux pump, known as P-glycoprotein (Pgp), capable of extruding toxic materials from the cell. In this work, resistance to UVA radiation, but not to UVC nor UVB, was observed in an MDR leukemia cell line. This cell line overexpresses Pgp. To study the role of Pgp in the resistance to UVA radiation, two MDR modulators or reversing agents (verapamil and cyclosporin A) capable of blocking Pgp activity were used. Cell viability was assessed and the techniques of flow cytometry and fluorescence microscopy were employed to measure the extrusion of rhodamine 123 by the efflux pump. The results show that MDR modulators did not modify the resistance to UVA radiation. Furthermore, although cell viability was not significantly altered, Pgp function was impaired after UVA treatment, suggesting that this glycoprotein may be a physical target for oxidative damage, and that other factors may be responsible for the UVA resistance. In agreement with this, it was found that the resistant cell line presented a higher catalase activity than the parental (non-MDR) cell line.
Onion (Allium cepa) is being studied as a potential anticancer agent, but little is known regarding its effect in multidrug resistance (MDR) cells. In this work, the cytotoxicity of crude onion extract (OE) and fractioned extract (aqueous, methanolic and ethyl acetate), as well as some onion compounds (quercetin and propyl disulfide) were evaluated in Lucena MDR human erythroleukemic and its K562 parental cell line. The capacity of OE to induce apoptosis and/or necrosis in these cells, the possible participation of oxidative stress and DNA damage were also assessed. Similar sensitivities were obtained for both tumoral cells, however only OE caused significant effects in the cells. In K562 cells, a significant increase of apoptosis was verified while the Lucena cells experienced a significant increase of necrosis. An antioxidant capacity was verified for OE discarding oxidative damage. However, OE provoked similar significant DNA damage in both cell lines. Thus, the OE capacity to overcome the MDR phenotype suggests anti-MDR action of OE.
The objective of this study was to evaluate the time-course effects of UV-B exposure on expression of genes involved in the DNA repair system of zebrafish (Danio rerio) hepatocytes, a highly competent species in terms of damage repair induced by UV radiation. For gene expression analysis (RT-PCR), cells were exposed to 23.3 mJ cm )2 UV-B, which was the dose that affected viable cell number (reduction of 30% when compared with the control group) and produced no visual alteration on cell morphology. The early response observed (6 h) showed induction in the expression of the CDKI gene (cyclin-dependent kinase inhibitor) and genes related to DNA damage repair (mainly XPC and DDB2), while the late response observed (24 h) was more related to up-regulation of p53 and genes involved in cell cycle arrest (gadd45a, cyclinG1). In all times analyzed, the antiapoptotic gene Bcl-2 was down-regulated. Another interesting result observed was the up-regulation of the Apex-1 gene after UV-B exposure, which could indicate the induction of oxidative lesions in the DNA molecule. In conclusion, these results demonstrate an activation of the DNA repair system in hepatocytes of zebrafish exposed to UV-B radiation, mainly involving the participation of p53.
Pigment dispersion in chromatophores as a response to UV radiation was investigated in two species of crustaceans, the crab Chasmagnathus granulata and the shrimp Palaemonetes argentinus. Eyestalkless crabs and shrimps maintained on either a black or a white background were irradiated with different UV bands. In eyestalkless crabs the significant minimal effective dose inducing pigment dispersion was 0.42 J/cm(2) for UVA and 2.15 J/cm(2) for UVB. Maximal response was achieved with 10.0 J/cm(2) UVA and 8.6 J/cm(2) UVB. UVA was more effective than UVB in inducing pigment dispersion. Soon after UV exposure, melanophores once again reached the initial stage of pigment aggregation after 45 min. Aggregated erythrophores of shrimps adapted to a white background showed significant pigment dispersion with 2.5 J/cm(2) UVA and 0.29 J/cm(2) UVC. Dispersed erythrophores of shrimps adapted to a black background did not show any significant response to UVA, UVB or UVC radiation. UVB did not induce any significant pigment dispersion in shrimps adapted to either a white or a black background. As opposed to the tanning response, which only protects against future UV exposure, the pigment dispersion response could be an important agent protecting against the harmful effects of UV radiation exposure.
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