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Canna~Fangled Abstracts

Synthetic cannabinoid quinones: Preparation, in vitro antiproliferative effects and in vivo prostate antitumor activity.

By October 23, 2013November 1st, 2023No Comments
[Epub ahead of print]

pm2Synthetic cannabinoid quinones: Preparation, in vitro antiproliferative effects and in vivo prostate antitumor activity.

Source

Instituto de Química Médica, CSIC, Calle Juan de la Cierva, 3, 28006 Madrid, Spain.

Abstract

Chromenopyrazolediones have been designed and synthesized as anticancer agents using the multi-biological target concept that involves quinone cytotoxicity and cannabinoid antitumor properties. In cell cytotoxicity assays, these chromenopyrazolediones have antiproliferative activity against human prostate cancer and hepatocellular carcinoma. It has been shown that the most potent, derivative 4 (PM49), inhibits prostate LNCaP cell viability (IC50 = 15 μM) through a mechanism involving oxidative stress, PPARγ receptor and partially CB1 receptor. It acts on prostate cell growth by causing G0/G1 phase arrest and triggering apoptosis as assessed by flow cytometry measurements. In the in vivo treatment, compound 4 at 2 mg/kg, blocks the growth of LNCaP tumors and reduces the growth of PC-3 tumors generated in mice. These studies suggest that 4 is a good potential anticancer agent against hormone-sensitive prostate cancer.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.

KEYWORDS:

Antiproliferative, Antitumor, Cannabinoid, Chromenopyrazoledione, EBNA, Electrochemistry, Epstein–Barr virus nuclear antigen, FITC, HT-29, HepG2, LNCaP, PBS, PC-3, PI, Prostate cancer, Quinone, ROS, S.D., S.E., TBAP, fluorescein isothiocyanate, heptoblastoma, human colon adenocarcinoma, lymph node carcinoma prostate, phosphate buffered saline, propidium iodide, prostate cancer, reactive oxygen species, standard deviation, standard error, tetrabutylammonium perchlorate

PMID:

24141201
[PubMed – as supplied by publisher] elsevier

Graphical abstract

Keywords

  • Cannabinoid;
  • Quinone;
  • Prostate cancer;
  • Antitumor;
  • Chromenopyrazoledione;
  • Antiproliferative;
  • Electrochemistry

Abbreviations

  • LNCaP, lymph node carcinoma prostate;
  • PC-3, prostate cancer;
  • HepG2, heptoblastoma;
  • HT-29, human colon adenocarcinoma;
  • ROS, reactive oxygen species;
  • EBNA, Epstein–Barr virus nuclear antigen;
  • TBAP, tetrabutylammonium perchlorate;
  • PBS, phosphate buffered saline;
  • S.D., standard deviation;
  • S.E.,standard error;
  • FITC, fluorescein isothiocyanate;
  • PI, propidium iodide

Figures and tables from this article:

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Fig. 1. Quinone structures related to cannabinoids.
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Fig. 2. Cyclic voltammetric curves of 1 mM 4 sweep rates ranging from 0.1 to 2 V/s in 100% DMSO with 0.1 M TBAP.
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Fig. 3. ESR experimental and simulated spectrum of 4 in DMSO.
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Fig. 4. Chromenopyrazolediones 4–6 decrease human cancer cell viability. Human hepatocellular carcinoma HepG2 and human prostate cancer LNCaP and PC-3 cells were incubated for 48 h with increasing doses of the tested compounds. Cell viability was determined by MTT. Data are the mean ± S.D. of two different experiments performed in triplicate.
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Fig. 5. Chromenopyrazoledione 4 induces cell cycle arrest inhuman prostate cancer cells. Cell cycle analysis of human prostate LNCaP and PC-3 cells treated with the IC50 (15 μM) of 4 for 24 h. Cells were stained with IP and analyzed by flow cytometry. Figure is representative of other two performed in duplicate.

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Fig. 6. Chromenopyrazoledione 4 induces apoptosis in human prostate cancer cells. Evaluation of apoptosis by annexin V-FITC/PI staining followed by flow cytometric analysis. Representative plots of annexin V-FITC/PI staining of LNCaP or PC-3 cells cultured in the presence of the IC50 (15 μM) of 4 for 24 h are shown. Data showing the percentage of late apoptotic cells (upper right quadrant) are the mean ± S.D. of three different experiments performed in duplicate.

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Fig. 7. Signaling pathways involved in antiproliferative effect produced by compound 4. LNCaP cells were incubated for 48 h with vehicle (control) or with 4 at IC50 dose (20 μM) in presence or not of different inhibitors (CB1 antagonist, SR1; CB2antagonist, SR2; PPARγ antagonist, GW 9662; and the antioxidant N-acetylcysteine, NAC). Cell viability was determined by MTT. Results represent the mean ± S.E. of four different experiments performed in duplicate. *p ≤ 0.05 compared with Student’s test versus NAC treated cells and #p ≤ 0.05 compared with Student’s test versus the compound alone.
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Fig. 8. In vivo antitumoral effect of compound 4. Athymic nude mice were injected s.c. in the right flank with either LNCaP (A) or PC-3 (B) cells and four weeks later (day 0) treated during 15 days with vehicle (control) or 2 mg/kg of 4. Treatments were administered intraperitoneally every day. Tumor growth curves are represented in the graph. Results represent the mean ± S.E. of eight mice in each group. A representative dissected tumor after the treatment is shown on the right.
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Scheme 1. Oxidation of chromenopyrazoles to the corresponding quinone derivatives 4–6 Reaction conditions: (i) 3,3-dimethylacrylic acid, CH3SO3H, P2O5, 70 °C, MW, 10 min; (ii) NaH, THF, MW, 46 °C, 20 min then ethyl formate, THF, MW, 46 °C, 20 min; (iii) H2N–NHR2, EtOH, 16 h, room temperature; (iv) [bis(trifluoroacetoxy)iodo]benzene, MeCN/H2O (6:1), 15 min, room temperature.
Table 1. Binding affinity of quinoid derivatives of chromenopyrazoles 4–6 and the reference cannabinoid WIN55,212-2 forhCB1 and hCB2 cannabinoid receptors.
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Table 2. Predicted ADME parameters in silico calculated for compound 4.
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