Pharmacological activities of natural triterpenoids and their therapeutic implications

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae).

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway

Chemoresistance in solid tumours.

Pentacyclic triterpenes from Chrysobalanaceae species: cytotoxicity on multidrug resistant and sensitive leukemia cell lines

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.

http://www.scielo.br/pdf/aabc/v73n1/v73n1a07.pdf

Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1

A multidrug resistant (MDR) cell line, derived from the human leukaemic cell K562 and selected for its resistance to Vincristine, was shown to be resistant to Thapsigargin (TG). A concentration of 50 nM TG was toxic to K562 cells whereas the MDR cell line, known as Lucena I cells, survived unaffected for up to seven days in culture. Similarly, no intracellular Ca2+ mobilization was observed in the MDR cell line treated with TG. This effect was not a result of TG extrusion by P glycoprotein (Pgp), as no mobilization was observed even in the presence of the Pgp inhibitors Verapamil (5 μM) and Cyclosporin A (0.16 μM). In the present study, both cell lines expressed comparable levels of Bcl-2 making it unlikely that Bcl-2 was involved in this process. Similarly, no overexpression of the endoplasmic reticulum Ca2+ ATPase (SERCA) could be detected in the MDR cell line and Ca2+ uptake by vesicles of the two cell types were equally sensitive to TG. These results confirm that MDR cells do not mobilize Ca2+ in the presence of TG but go against the possibility that this might be due to TG extrusion or to the overexpression of a resistant SERCA isoform.

Resistance to thapsigargin-induced intracellular calcium mobilization in a multidrug resistant tumour cell line.

A serious problem in cancer chemotherapy involves the generation of multidrug resistance (MDR). This phenomenon represents cross-resistance among a number of drugs, unrelated structurally or functionally, and is one of the major reasons for chemotherapy failure. MDR is associated to the overexpression of the mdr 1 gene which encodes a 170kDa plasma membrane glycoprotein known as P glycoprotein (Pgp) (Chen et al., 1986; Juliano and Ling, 1976; Riordan et al., 1985) and it has been demonstrated that overexpression of this protein is sufficient to confer cellular resistance (Ueda et al. 1987). Pgp functions as an ATP-dependent efflux pump capable of extruding antineoplastic agents to the outside of the cell reducing their intracellular levels. Structurally, Pgp is a transmembrane protein arranged in two homologous halves, each half containing an ATP binding site facing the cytoplasm, and with twelve hydrophobic regions forming the transmembrane loops (Gottesman and Pastan, 1993).

Modulation of P-Glycoprotein on Tumour Cells

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Karen Wagner-Souza

Papers

Pentacyclic triterpenes from Chrysobalanaceae species: cytotoxicity on multidrug resistant and sensitive leukemia cell lines

Multidrug resistance in tumour cells: characterization of the multidrug resistant cell line K562-Lucena 1

Resistance to thapsigargin-induced intracellular calcium mobilization in a multidrug resistant tumour cell line.

Modulation of P-Glycoprotein on Tumour Cells

Ciclosporina A e seus análogos como reversores da resistência a múltiplas drogas em células tumorais