Marine Natural Products as Breast Cancer Resistance Protein Inhibitors

Abstract

Breast cancer resistance protein (BCRP) is a protein belonging to the ATP-binding cassette (ABC) transporter superfamily that has clinical relevance due to its multi-drug resistance properties in cancer. BCRP can be associated with clinical cancer drug resistance, in particular acute myelogenous or acute lymphocytic leukemias. The overexpression of BCRP contributes to the resistance of several chemotherapeutic drugs, such as topotecan, methotrexate, mitoxantrone, doxorubicin and daunorubicin. The Food and Drugs Administration has already recognized that BCRP is clinically one of the most important drug transporters, mainly because it leads to a reduction of clinical efficacy of various anticancer drugs through its ATP-dependent drug efflux pump function as well as its apparent participation in drug resistance. This review article aims to summarize the different research findings on marine natural products with BCRP inhibiting activity. In this sense, the potential modulation of physiological targets of BCRP by natural or synthetic compounds offers a great possibility for the discovery of new drugs and valuable research tools to recognize the function of the complex ABC-transporters.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…The mechanisms of their antitumor effects include topoisomerase I poisoning, inhibition of PKC, PKA, pyruvate dehydrogenase kinase (PDK)/cyclin B, and cyclin-dependent kinase 5 (CDK5)/p5 [144,145]. The naturally occurring arcyriaflavin (63) and indolcarbazole K252c or staurosporin aglycone (64, Figure 12) showed the most potent effects in BCRP inhibition in the BCRP-transferred HEK-293 cell line, with low toxicity in BCRP-transfected cells, and reduced the relative resistance of ABCG2-transfected cells SN-38 [29,146]. Bisindolylmaleimide analogs 65-69 ( Figure 12) were found to be able to inhibit [ 125 I]iodoarylazidoprazosin labeling of BCRP by 65% to 80% at 20 μM [146].…”

“…There are already several reviews which highlighted the importance of marine natural products in cancer and, in particular, as P-gp modulators [29,35,[39][40][41][42][43]. However, this review aims to describe not only the effects of the most valuable scaffolds from marine natural products and analogs in overcoming MDR but also their synthetic pathways.…”

“…Recently, there has been a proposal of a new generation of ABC inhibitors which focuses on natural products and natural product mimics [28][29][30], peptidomimetics [31], surfactants and lipids [32], and dual ligands [20]. While the traditional sources of terrestrial plants and microbes will undoubtedly continue to yield valuable new bioactive agents, it is even more important to explore all available pools of molecular diversity.…”

“…Marine natural products are one of the most interesting targets for global drug discovery since they not only possess structural and chemical uniqueness but also represent novel scaffolds for drug development [34]. Marine natural products have also been studied and tested alongside with synthetic compounds as ABC transporter inhibitors [29,[35][36][37][38]. The development of anticancer drugs from marine compounds is one of the most promising approaches in drug discovery with therapeutic agents in clinical practice, such as the anticancer trabectedin [37].…”

Recent advances in isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids of marine origin

“…These chemical substances, which are produced within their system, are called ‘marine natural products.’ Usually existing as secondary metabolites in marine invertebrates such as sponges, bryozoans, tunicates, and ascidians, marine natural products help these organisms by deterring their predators or paralyzing their prey [7, 8]. Upon the release of these compounds into their surroundings, they are usually rapidly diluted by water.…”