Stereo-Selective Pharmacokinetics of Ilimaquinone Epimers Extracted from a Marine Sponge in Rats

Son, Heebin; Noh, Keumhan; Park, InWha; Na, MinKyun; Oh, Sangtaek; Shin, Beom Soo; Kang, Wonku

doi:10.3390/md17030171

Cited by 4 publications

(4 citation statements)

References 18 publications

(28 reference statements)

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“…The antimicrobial, anticancer, anti-inflammatory, and protein transport-inhibitory effects of IQ have been reported [ 14 , 16 , 27 , 28 ]. The pharmacokinetic features of IQ were also previously studied in rat models [ 29 , 30 ]. In a previous study, the GI 50 values of IQ on PC-3, DU145, LNCaP, MG63, A549, and Hep3B cells were found to be 2.6 to 19.8 μM at 48 h [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Kwak

Han

et al. 2020

IJMS

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In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

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Section: Discussionmentioning

confidence: 99%

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Kwak

Han

et al. 2020

IJMS

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“…The AUC for IQ was approximately six-fold higher than that of epi-IQ after i/v injection. After peroral administration, C max for IQ was 11.6-fold higher compared with epi-IQ, whereas the T max for both substances was almost the same ( Table 2 ) [ 46 ]. The absorption of ilimaquinone after the peroral administration of the mixture seems to be faster compared with single-compound administration [ 117 ].…”

Section: Pharmacokinetics Studies In Animalsmentioning

confidence: 99%

“…Although the T 1/2 values for both iso-forms were equal after mixture administration, the clearance of epi-IQ was much greater ( Table 2 ). The absolute bioavailability after peroral administration of the mixture was calculated as 38% and 13% for IQ and epi-IQ, respectively [ 46 ]. The results of this study highlight the importance of pharmacokinetic investigations of stereoisomers.…”

Section: Pharmacokinetics Studies In Animalsmentioning

confidence: 99%

Pharmacokinetics of Marine-Derived Drugs

et al. 2020

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Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has attracted increasing interest in recent decades due to its effective and potential contribution to the selection of rational dosage recommendations and the optimal use of the therapeutic arsenal. In general, pharmacokinetics studies how drugs change after administration via the processes of absorption, distribution, metabolism, and excretion (ADME). This review provides a summary of the pharmacokinetics studies of marine-derived active compounds, with a particular focus on their ADME. The pharmacokinetics of compounds derived from algae, crustaceans, sea cucumber, fungus, sea urchins, sponges, mollusks, tunicate, and bryozoan is discussed, and the pharmacokinetics data in human experiments are analyzed. In-depth characterization using pharmacokinetics is useful for obtaining information for understanding the molecular basis of pharmacological activity, for correct doses and treatment schemes selection, and for more effective drug application. Thus, an increase in pharmacokinetic research on marine-derived compounds is expected in the near future.

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“…With regard to pharmacokinetics, a recent study performed in rats reported an oral bioavailability of 45% after administration of 10 mg IQ /kg body weight (b.w.) [55]. The maximum plasma concentration determined for single oral administration was 0.94 µg/mL, which corresponds to approximately three µM.…”

Section: Discussionmentioning

confidence: 88%

Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer

Jiso

Demuth

Bachowsky

et al. 2021

Cancers

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Colorectal cancer (CRC) is a frequently occurring malignant disease with still low survival rates, highlighting the need for novel therapeutics. Merosesquiterpenes are secondary metabolites from marine sponges, which might be useful as antitumor agents. To address this issue, we made use of a compound library comprising 11 isolated merosesquiterpenes. The most cytotoxic compounds were smenospongine > ilimaquinone ≈ dactylospontriol, as shown in different human CRC cell lines. Alkaline Comet assays and γH2AX immunofluorescence microscopy demonstrated DNA strand break formation in CRC cells. Western blot analysis revealed an activation of the DNA damage response with CHK1 phosphorylation, stabilization of p53 and p21, which occurred both in CRC cells with p53 knockout and in p53-mutated CRC cells. This resulted in cell cycle arrest followed by a strong increase in the subG1 population, indicative of apoptosis, and typical morphological alterations. In consistency, cell death measurements showed apoptosis following exposure to merosesquiterpenes. Gene expression studies and analysis of caspase cleavage revealed mitochondrial apoptosis via BAX, BIM, and caspase-9 as the main cell death pathway. Interestingly, the compounds were equally effective in p53-wild-type and p53-mutant CRC cells. Finally, the cytotoxic activity of the merosesquiterpenes was corroborated in intestinal tumor organoids, emphasizing their potential for CRC chemotherapy.

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Stereo-Selective Pharmacokinetics of Ilimaquinone Epimers Extracted from a Marine Sponge in Rats

Cited by 4 publications

References 18 publications

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Pharmacokinetics of Marine-Derived Drugs

Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer

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