Selectivity and Potency of Microcystin Congeners against OATP1B1 and OATP1B3 Expressing Cancer Cells

Niedermeyer, Timo H. J.; Daily, Abigail; Swiatecka-Hagenbruch, Monika; Moscow, Jeffrey A.

doi:10.1371/journal.pone.0091476

Cited by 66 publications

(45 citation statements)

References 91 publications

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“…OATP1B3 mediates the transport of several endogenous substrates including hormones (E3S, DHEA-S, testosterone), cancer drugs (methotrexate, imatinib, paclitaxel, SN-38, rapamycin, docetaxel, doxorubicin), microcystins, and MRI contrast agents (gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)) (33,97). Similar to the decreased expression of the closely related member OATP1B1 in HCC, OATP1B3 expression was shown to be decreased in primary and metastatic liver cancers (39,41,98).…”

Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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Abstract. The superfamily of organic anion-transporting polypeptides (OATPs, gene symbol SLCO) includes important transporters handling a variety of endogenous and xenobiotic substrates. Currently, 11 human OATPs are known and their substrates include endogenous hormones and their conjugates, anticancer drugs, and imaging agents. The contribution of OATPs to the in vivo disposition of these substrates has been extensively investigated. An accumulating body of evidence also indicates that the expression of some OATPs may be up-or downregulated in several types of cancers, suggesting potential pathogenic roles during the development and progression of cancer. Given that the role of OATPs in handling cancer therapeutics has been already covered by several excellent reviews, this review will focus on the recent progresses on the topic, in particular the role of OATPs in the disposition of anticancer drugs, the impact of OATP genetic variations on the function of OATPs, and the OATPs differentially expressed in cancer and their potential roles in cancer development, progression, and treatment.

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Section: Oatp1b3 (Gene Symbol Slco1b3)mentioning

confidence: 99%

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Thakkar

Lockhart

Lee

2015

AAPS J

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“…MCs are cyclic hepatopeptides composed of seven amino acids with the general structure of cyclo D-Ala 1 -X 2 -D-MeAsp 3 -Z 4 -Adda 5 -D-Glu 6 -Mdha 7 , in which X and Z are variable Lamino acids, D-MeAsp is D-erythro methylaspartic acid, Adda is a unique 3-amino-9-methoxy-2, 6,8-trimethyl-10-phenyl-deca-4,6-dienoicacid, and Mdha is N-methyldehydroalanine (Figure 1 A) ( Van Apeldoorn et al 2007). Currently, more than 100 different congeners of MCs have been identified (Niedermeyer 2014). The variants typically vary at the X and Z-amino acids positions, the presence or absence of methyl group on D-MeAsp and / or Mdha and the substations of other moieties (Rinehart et al 1994, Sivonen 1996, Namikoshi et al 1998.…”

Section: Introductionmentioning

confidence: 99%

Still challenging: the ecological function of the cyanobacterial toxin microcystin – What we know so far

2017

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Microcystins (MCs) are the most commonly studied cyanotoxins. While these past studies have mainly focused on the toxicity of MCs, the evolutionary history of life has shown that toxicity can be considered as an assigned role to MCs. Nowadays, there is a growing interest in understanding the importance of cyanotoxins in any of the physiological processes or beyond at the ecological level. This review evaluates the variously proposed intracellular and extracellular functions of MCs and how they benefit the producing cyanobacterium. However, the strain-specific and divergent laboratory and field results obtained to date have made it difficult to generalize.Recent studies demonstrated a correlation between dissolved inorganic carbon (DIC) and the growth and MC production of M. aeruginosa. In a competitive study, the effect of low and high DIC (0.365 and 7.658 mmol l -1 KHCO3) on M. aeroginosa toxic and non-toxic strains, FACHB 912 and FACHB 469, co-cultured with green algae Chlamydomonas microsphaera were investigated. The growth of M. aeruginosa toxic and non-toxic strains was negatively affected by DIC without any significant changes in the chlorophyll content; however, the photosynthesis efficiency and chlorophyll content of green algae decreased. The results proposed that M. aeruginosa might be more adapted to low DIC condition (Zhang et al. 2012). Increased dissolved inorganic carbon had an adverse effect on the frequency of toxic Microcystis and MCs concentration in Lake Chaohu, China as well (Yu et al. 2014). Deficiency of intracellular inorganic carbon resulted in an increase in MC production of M. aeruginosa PCC 7806. Moreover, the toxic

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“…Microcystins (MCs) are a group of cyclic heptapeptides that are produced by cyanobacteria. To date, more than 90 structural variants have been identified . Among these, microcystin‐LR (MC‐LR) is the most common and toxic type.…”

Section: Introductionmentioning

confidence: 99%

Microcystin‐LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase

Liu

Zhang

et al. 2017

Environmental Toxicology

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Microcystin-LR (MC-LR) is a cyanobacteria-derived heptapeptide that has been commonly characterized as a hepatotoxin. Although the liver is a primary organ in glucose homeostasis, the effect of MC-LR on glucose metabolism remains unclear. In this study, the human liver cell line HL7702and ICR mice were exposed to various concentrations of MC-LR for 24 h, and the proteins involved in insulin signaling were investigated. The results showed that MC-LR treatment induced the hyperphosphorylation of insulin receptor substrate 1 (IRS1) at several serine sites, S307, S323, S636/639, and S1101 in HL7702 cells, and S302, S318, S632/635, and S1097 in mice livers. In addition, the activation of S6K1 was demonstrated to play an important role in MC-LR-induced IRS1 hyperphosphorylation at several serine sites. Decreased levels of total IRS1 were observed in the mice livers, but there was no significant change in HL7702 cells. MC-LR also induced glycogen synthase (GS) hyperphosphorylation at S641 (inactivating GS) both in vitro and in vivo, even glycogen synthase kinase 3, a well-known GS kinase, was inactivated after MC-LR treatment.Moreover, MC-LR could block insulin-induced GS activation. In addition, glucose transport in liver cells was not impacted by MC-LR either with or without insulin stimulation. Our study implies that MC-LR can interfere with the actions of IRS1 and GS in insulin signaling and may have a toxic effect on glucose metabolism in the liver. K E Y W O R D Sglycogen synthase, insulin receptor substrate 1, microcystin-LR, S6K1

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Selectivity and Potency of Microcystin Congeners against OATP1B1 and OATP1B3 Expressing Cancer Cells

Cited by 66 publications

References 91 publications

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

Still challenging: the ecological function of the cyanobacterial toxin microcystin – What we know so far

Microcystin‐LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase

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