Inhibition of Multidrug Resistance of Cancer Cells by Natural Diterpenes, Triterpenes and Carotenoids

Abstract

The multidrug resistance (MDR) proteins are member of the ATP-binding cassette superfamily and are present in a majority of human tumors. Their activity is a crucial factor leading to therapeutic failure. It is likely that compounds which inhibit the function of the MDR-efflux proteins such as MDR1 will improve the cytotoxic action of anticancer chemotherapy. Therefore, a search for MDR reversing compounds was conducted among three classes of plant derived compounds such as diterpenes, triterpenes and carotenoids in a hope to find inhibitors without adverse effects in these natural compounds. The inhibition of efflux activity was determined by measuring the accumulation of substrate analogues such as rhodamine in tumor cells in the presence of potential inhibitors. Thus we determined the effect of structurally unrelated diterpenes, triterpenes and carotenoids on reversal of multidrug resistance in MDR-1 gene-transfected L1210 mouse lymphoma cells and MDR mediated multidrug resistance of human breast cancer cells MDA-MB-231 (HTB-26) and MCF-7. The majority of diterpenes, cycloartane triterpenes and carotenoids isolated from vegetables and medicinal plants were able to enhance rhodamine 123 accumulations of MDR-cells. Synergistic interaction was found between epirubicine and resistance modifier terpenoids in vitro. It is supposed that these MDR modulators bind into transmembrane domains and the action of ABC transporters is inhibited by induced conformational changes.

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…This is especially true if a patient is relapsing after a chemotherapy treatment because the remaining cancer cells are being selected for resistance, generally due to the increased expression of the ABC transporters [49]. Many pharmaceutical ABC transporter inhibitors are able to decrease drug efflux from cancer cells in vitro, but most tend to have serious and deleterious side effects in vivo, and none is currently approved for inclusion into chemotherapy treatments [19].…”

“…Treatment with SJW is able to reduce plasma levels of these drugs by up to 57% in healthy human volunteers, which could potentially lead to subtherapeutic levels and selective pressure for the creation of resistant viral particles in AIDS patients [62]. Recent work by Molnar et al [49] has shown that a wide range of naturally occurring lipophilic phytochemicals (diterpenes, triterpines and carotenoids) were able to inhibit human Pgp in vitro at the low lg/ml range, whereas other combinations had positive synergistic activity. Using purified polyphenols on Pgp overexpressing cells in vitro, Patel et al [59] showed that quercetin, hypericin and kaempferol were able to increase the cellular uptake of ritonavir by five-to eightfold.…”

1-[4-(2-Aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-oxopiperidines: A novel series of highly potent revertants of P-glycoprotein associated multidrug resistance

“…88 and 5.02, respectively. 24 A number of studies revealed the high lipophilicity of various MDR-reversal agents 25,26 ; for example, the calculated logP values of a number of 1,4-dihydropyridines which reverse MDR were in the region of 5.1-7.5. 27 The calculated logP values of the compounds in series 4-9 and verapamil are presented in Table 1 …”

“…Thus groups which are lipophilic and have MR values of approximately 5-6 should be placed in the arylidene aryl rings, for example, the trifluoro-methyl substituent has π and MR values of 0.88 and 5.02, respectively. 24 A number of studies revealed the high lipophilicity of various MDR-reversal agents 25,26 ; for example, the calculated logP values of a number of 1,4-dihydropyridines which reverse MDR were in the region of 5.1-7.5. 27 The calculated logP values of the compounds in series 4-9 and verapamil are presented in Table 1 The potential of these compounds as MDR revertants will be enhanced if bioactivity is displayed at lower concentrations than 4 μg/ml and reversal of MDR occurs in a different species and another neoplastic disease.…”

“…25 The functionally active conformation of P-gp depends on the integrity of the membrane bilayer in which P-gp is embedded. Due to the existence of 12 transmembrane domains of P-gp, the co-crystallization of MDR inhibitors and P-gp is not possible thereby precluding direct evidence of ligand binding.…”