Identification of Important Compounds Isolated from Natural Sources that Have Activity Against Multidrug-resistant Cancer Cell Lines: Effects on Proliferation, Apoptotic Mechanism and the Efflux Pump Responsible for Multi-resistance Phenotype

Abstract

Abstract. The focus of this mini-review is to identify non-toxic compounds isolated from natural sources (plants) that exhibit specific activity against efflux pumps of specific multidrugresistant (MDR) cancer cell lines, inhibit proliferation of the MDR cancer cell lines and inhibit the activity of overexpressed efflux pumps of the MDR cancer cell line.Therapy of cancer, if not completely effective, results in the overexpression of genes that code for efflux pumps that extrude the noxious agent (anticancer drug) before it reaches its intended target of the cancer cell (1). The overexpressed efflux pump renders the cancer cell immune to not only the initial drug used in therapy but to a wide range of unrelated noxious compounds (1). The arising of this multidrugresistant (MDR) phenotype makes therapy highly problematic and the end result is that the patient succumbs to the disease (1). Therefore, it is the consensus of many that therapy of MDR cancer may succeed if the responsible efflux pump is inhibited from its activity, therefore, affording the increased concentration of anticancer drug to a level consistent with its toxic targeted action needed to kill the cancer cell. To this extent, over 100,000 synthetic compounds for activity against the known efflux pumps of cancer cell types have been screened by the National Cancer Institute (USA) and, to date, not a single inhibitor has found its way toward successful therapy of MDR cancer. In fact, because normal counter type cells have a fully functional efflux pump, albeit at a much lower level of activity, clinical trials with selected efflux pump inhibitors have produced high toxicity and even death.During the past two decades, traditional medicine has become a source for the identification of plants that harbor compounds that may have important potential for the therapy of cancer. With respect to the laboratory of one of the authors of this mini-review (JM), literally, hundreds of plants have been studied for their activity against specific targets of the cancer cell and it is the focus of this mini-review to identify selected compounds that have no toxicity at the level of their in vitro study and which have activity against proliferation or induction of the apoptotic mechanism or the efflux pump responsible for the phenotype of the MDR cancer cell. Targets of MDR Cancer CellsProliferation. Proliferation is affected by many drugs and, although the search for non-toxic compounds that inhibit proliferation was initiated more than 60 years ago, remains the focus of most studies; however, the inhibition of proliferation by compounds isolated from natural sources will not be discussed here at the level of its mechanism. Rather, suffice to say that our observations for antiproliferative activity as presented in the text remain, for the 5665

Jatrophane and rearranged jatrophane-type diterpenes: biogenesis, structure, isolation, biological activity and SARs (1984–2019)

“…Ferreira et al (2014) in a review article provided a summary (2001-2013) of anticancer compounds from Euphorbia and Momordica species comprising diterpenes, triterpenes, and phenolic derivatives, particularly for their P-gp inhibition ability . In another study, Amaral et al (2016) prepared a mini-review focusing on the property of MDR cancer cells (proliferation, apoptotic mechanism, efflux pumps) affected by bioactive compounds.…”

L1210 Cells Overexpressing ABCB1 Drug Transporters Are Resistant to Inhibitors of the N- and O-glycosylation of Proteins

“…Processes of tissue cell carcinogenesis are frequently associated with the strong remodelation of cell sugar composition [ 1 , 2 ] detectable based on various lectins, which could be used as specific features for differential diagnostics [ 3 , 4 ]. Neoplastic cells could develop resistance to a diverse group of unrelated drugs known as multidrug resistance (MDR), representing a specific cell phenotype secured via several different mechanisms [ 5 ] and creating a real obstacle for the effective chemotherapy of cancer [ 6 ]. MDR in neoplastic cells has frequently been associated with a massive alteration of cell sugar metabolism/contents [ 7 , 8 , 9 ].…”

Identification of Triterpenes and β-sitosterol in the Bark of Plane Tree Extracts

“…Triterpenenoids are an important class of natural plant materials with many important biological effects [1]. They are promising in the treatment of certain types of cancer by the inhibition of the replication of cancer cells by affecting the S phase of DNA synthesis [2] and they often show high anti-inflammatory, antiviral and antioxidant activities. Among these compounds the lupine-type pentacyclic triterpenes, like betulin (3-lup-20(29)-ene-3β,28-diol), betulinic aldehyde and betulinic acid are particularly interesting [3] due to their anticancer [4], antiviral [5], antibacterial, anti-inflammatory, antimalarial, anthelmintic and antioxidant activities [6].…”