Isoquinolinequinone<i>N</i>-oxides as anticancer agents effective against drug resistant cell lines

Kruschel, Ryan D.; Buzid, Alyah; Khandavilli, U. B. Rao; Lawrence, Simon E.; Glennon, Jeremy D.; McCarthy, Florence O.

doi:10.1039/c9ob02441g

Cited by 19 publications

(24 citation statements)

References 46 publications

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“…Over the last years or so, the use of 1,4-quinone, an important source of natural products, has enabled the design of efficient and active molecules with improved pharmacological properties in the search of new molecules with cytotoxic activity [ 11 , 12 , 13 , 14 , 15 , 16 ]. The 1,4-quinone and 1,4-naphthoquinone moieties are well-represented in bioactive natural structures and their anticancer effects, including anti-colorectal cancer properties, have been documented in several studies.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 μM compared to cisplatin (IC50 = 26.65 ± 7.85 μM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.

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Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

et al. 2022

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“…Their arylamino derivatives have attracted interest because of their antitumor effects on AGS human gastric adenocarcinoma cells (CRL-1739), HL-60 human leukemia cells (CCL-240), SK-MES-1 human lung cancer cells (HTB-58), and J82 human bladder carcinoma cells (HTB-1) [3], and antifungal and antibacterial activities [4,5]. Besides, recently has been reported the antitumor activities of AQ-1 against resistant breast cancer (BC) cell line MDA-MB 231 [6], among others. Another analog, AQ-2, also shows selective cytotoxicity on this metastatic BC cell line by activating AMP-activated kinase (AMPK), downregulating unfolded protein response pathway, and inhibiting mTOR signaling [7].…”

Section: Introductionmentioning

confidence: 99%

FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells

et al. 2021

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Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells.

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“…Aminoquinones continue to attract significant attention as drug candidates because of their broad biological activity profiles and easy accessibility [ 9 , 10 , 11 ]. Many studies have been conducted on the biological activities of quinones, particularly focusing on the anticancer and antimicrobial properties of aminoquinones [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Recent developments in our group have contributed significantly to searching and identifying the lead molecules based on natural products, mainly focusing on the antiproliferative [ 20 , 21 , 22 ] and antimicrobial profiles [ 23 , 24 ] of quinones.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

et al. 2022

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Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

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IsoquinolinequinoneN-oxides as anticancer agents effective against drug resistant cell lines

Abstract: 6- and 7-Substituted isoquinoline N-oxides are identified as redox active, adduct forming, anticancer agents and effective against drug resistant cell lines at nanomolar concentrations.

Cited by 19 publications

References 46 publications

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment

FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts by Redox Disruption in Breast Cancer Cells

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

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