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Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 1141-1146

A new acetylacetone derivative inhibits breast cancer by apoptosis induction and angiogenesis inhibition

1 Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan
2 Department of Chemistry, Hashemite University, Zarqa, Jordan
3 Department of Biology and Biotechnology, Hashemite University, Zarqa, Jordan

Date of Web Publication4-Oct-2019

Correspondence Address:
Wamidh H Talib
Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman 11931
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_948_17

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 > Abstract 

Aim: Cancer is one of the main causes of death worldwide. High mortality rates were reported among breast cancer patients which makes the development of new anticancer agents targeting breast cancer a priority. The synthesis of the compounds incorporating– N=N– group is an important field of research that may lead to the discovery of new anticancer drug.
Materials and Methods: In this work, we report the synthesis of a compound has O and N centers with the incorporation of the arylazo group (4-BrC6H4–N=N–) into acetylacetone to synthesize 3-(4-Bromo phenylazo)-2,4-pentanedione. Physical characteristics of the newly synthesized compound were determined by measuring electronic absorption spectra, nuclear magnetic resonances, and the infrared absorption spectrum. The inhibitory effect of the compound against breast cancer cell lines was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Its effect on angiogenesis was evaluated by measuring vascular endothelial growth factor (VEGF) levels in treated cells. The ability of the compound to induce apoptosis in cancer cells was tested by measuring caspase-3 activity, and its capacity to stimulate the immune system was evaluated by measuring the levels of interferon gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-10 cytokines in treated lymphocytes.
Results: Significant antiproliferative activity against breast cancer cell lines was observed in treated cells. Low levels of VEGF and high caspase-3 activity were observed in treated cells. Levels of IFN-γ, IL-2, and IL-4 were increased after treating lymphocytes with this compound.
Conclusion: 3-(4-Bromo phenylazo)-2,4-pentanedione is a promising anticancer agent that can inhibit breast cancer cells through apoptosis induction and angiogenesis inhibition. Further testing is needed to clearly determine the molecular mechanisms of the anticancer effect of this compound.

Keywords: 3-(4-Bromo phenylazo)-2, 4-pentanedione, angiogenesis inhibition, apoptosis, arylazo group, breast cancer, caspase-3, cell viability, vascular endothelial growth factor

How to cite this article:
Talib WH, Al-Noaimi M, Alsultan ES, Bader R, Qnais E. A new acetylacetone derivative inhibits breast cancer by apoptosis induction and angiogenesis inhibition. J Can Res Ther 2019;15:1141-6

How to cite this URL:
Talib WH, Al-Noaimi M, Alsultan ES, Bader R, Qnais E. A new acetylacetone derivative inhibits breast cancer by apoptosis induction and angiogenesis inhibition. J Can Res Ther [serial online] 2019 [cited 2020 Jul 7];15:1141-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/1141/251401

 > Introduction Top

Cancer is a heterogeneous group of diseases that may occur in any body part. During the past few decades, significant improvements were achieved in the battle against cancer. However, cancer continues to be one of the main causes of death worldwide.[1] Recent reports of the American Cancer Society showed the presence of 74 different types of cancer with breast cancer as the second most common type. The high mortality rates documented among breast cancer patients make this disease a major health concern and call for further research to develop new therapies.[2] The main conventional therapies for breast cancer include surgery, chemotherapy, hormonal therapy, and radiation. These therapeutic options are not highly effective in treating breast cancer, especially in advanced stages.[3] Therefore, identifying and testing of new agents that reduce the incidence of breast cancer and may cure it is a priority.

The synthesis of the compounds incorporating–N=N– group such as arylazobenzene,[4] arylazooxime,[5] arylazophenol,[6] arylazopyridine,[7] arylazoimidazole,[8] arylazopyrimidine,[9] and arylazoaniline,[10] and phenylazoimine [11],[12],[13],[14] is an important field of research. These compounds containing oxygen, nitrogen, and sulfur donor centers have been effectively used in modeling biomolecule, in exploring chemical electrochemical, catalytic activities and magnetic behaviors.[15],[16] Acetylacetone and its derivatives have many applications in the synthesis of metal complexes.[17],[18],[19],[20],[21],[22] Herein, in this work, we report the synthesis of a compound has O and N centers with the incorporation of the arylazo group (4-BrC6H4–N=N–) into acetylacetone to synthesize 3-(4-Bromo phenylazo)-2,4-pentanedione. The antiproliferative activity of this compound was tested on breast cancer cell lines. Its ability to induce apoptosis, modulate the immune system, and inhibit angiogenesis were also evaluated.

 > Materials and Methods Top

All the reagents and solvents were purchased from commercial sources and used as received. Acetylacetone (acac), 4-Bromo aniline, NaNO2 and were made available from Sigma-Aldrich. The following culture media were purchased from Sigma-Aldrich (Missouri, USA): Dulbecco's Modified Eagle's Medium and Roswell Park Memorial Institute (RPMI)-1640 medium.

Physical measurements

Electronic absorption spectra ultraviolet-visible spectroscopy (UV-Vis) for all samples are carried out in acetonitrile at room temperature using a diode array spectrophotometer instrument. Nuclear magnetic resonances (1 H and 13 C-NMR) spectra were measured using a Bruker-Avance 400 MHz spectrometer in CDCl3 solutions at room temperature. All chemical shifts are reported in ppm derived from an internal tetramethylsilane reference. Infrared (IR) absorption was measured using Bruker vertex. Elemental analysis was carried out using a Eurovector E. A.3000 instrument using copper sample tubes. Melting points were measured using a Stuart scientific melting apparatus (uncorrected ± 0.1°C).

Synthesis of compound (HL)

The diazotized solution of 4-Bromo aniline was prepared by adding ice cold of solution NaNO2 (0.552 g, 8.0 mmol) dropwise at 0°C–5°C to this ice cold solution of 4-Bromo aniline (1.38 g, 8.0 mmol) dissolved in 10 ml 12 N HCl. The resulting diazotized solution was kept in an ice bath. Separately, an ice cold solution of acetylacetone (0.801 g, 8 mmol) was prepared in 20 ml of 1:1 pyridine: Water solution. The diazotized solution was then slowly added to the cold pyridine solution with vigorous stirring. Stirring was continued for 30 min after the addition was complete. The whole mixture was then kept under refrigeration for 1 h. Yellow precipitate of L was obtained. The crude product was collected by filtration, washed thoroughly with water and recrystallized from ethanol. It was then filtered again and washed with cold ethanol. Finally, dried over CaCl2. Yield (2.04, 90%). Anal. Calc., for C11H11 BrN2O2: C, 46.67; H, 3.92; N, 9.89%. Found: C, 46.45; H, 3.82; N, 9.71%. UV–Vis in acetonitrile: λmax (nm) (ɛmax/M −1 cm −1): 375 (3.5 × 103), 250 (1.75 × 103). IR: ν (N = N) 1488, ν (C = C) 1620, ν (C = O) 1664 cm −1.1 H NMR (CDCl3,d ppm): 14.66 (s, 1H, OH), 7.51 (d, 2H, H1), 7.28 (d, 2H, H2), 2.6 (s, 3H, COCH3), 2.46 (s, 3H, H5), m.pis 122–125°C.

In vitro cell proliferation using MTT assay

The antiproliferative activity of 3-(4-Bromo phenylazo)-2,4-pentanedione was tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The procedure was conducted as previously described.[23] Briefly, Michigan Cancer Foundation-7 (MCF-7) and T47D (human breast carcinoma cell lines), as well as Vero (monkey kidney) normal cell lines were cultured in 96-well microplates (100 μl; 1.5 × 104 cells per well) in a medium-containing 10% fetal bovine serum (FBS), 1% L-glutamine, 1% penicillin-streptomycin, and 0.1% gentamycin. All cell lines were provided by the University of Jordan, Amman, Jordan. Cells were incubated for 24 h at 37°C in a 5% CO2 enriched atmosphere. After this, the cells were treated with increasing concentrations of 3-(4-Bromo phenylazo)-2,4-pentanedione (20–200 μM). Then, MTT was added to the wells according to the manufacturer's instructions (Sigma-Aldrich, Missouri, USA). Percentage survival was calculated using the following equation:

% Survival = treated cells absorbance/negative control absorbance × 100%

The calculated inhibitory concentration (IC50) represents the treatment concentration that showed a lethal effect on 50% of cells. Cells treated with cisplatin were used as a positive control and those incubated with culture medium alone were used as a negative control.

Determination of vascular endothelial growth factor expression in MCF-7 cells

MCF-7 cells were suspended at a concentration of 1.5 × 106 cell/10 ml RPMI and incubated for 48 h in three different tissue culture flasks. Tissue culture media were removed, and cultured cells were subjected to the following treatments: 42.5 μM of 3-(4-Bromo phenylazo)-2,4-pentanedione, 11 μm cisplatin, and a blank RPMI medium as a negative control. The concentration of cisplatin was selected based on a previous study of breast cancer.[24] The treated cultured cells were incubated for 48 h. After this, the medium in each flask was removed, and the cells were harvested using trypsin- ethylenediaminetetraacetic acid solution washed with phosphate buffered saline (PBS), and then centrifuged at 1500 RPM for 10 min.[25] Vascular endothelial growth factor (VEGF) expression in cancer cells was measured using mouse VEGF enzyme-linked immunosorbent assay (ELISA) kit (catalog # RAB0510; Sigma-Aldrich, Missouri, USA) according to the manufacturer's instructions.

Determination of caspase-3 activity in MCF-7 cells

After treatment with 45 μM of 3-(4-Bromo phenylazo)-2,4-pentanedione, cells (1 × 106/ml) were washed with ice-cold PBS and lysed with cell lysis buffer (caspase–3 assay kit, catalogue # ab39401; abcam, Missouri, USA). Samples were incubated on ice for 10 min and centrifuged in a microcentrifuge at 12,000 × g for 5 min at 4°C to precipitate the cellular debris. The caspase-3 activity in the supernatant was measured spectrophotometry using DEVD-p-nitroanilide as a substrate at 405 nm and according to the manufacturer's instructions provided with the assay kit.[26] Caspase 3 activity was measured at different time intervals (0, 6, 15, 24, and 48 h).

Detection of change in cytokines levels

Standard ethical guidelines for animal treatment were followed, and all of the experimental protocols were approved by the Research and Ethical Committee at the Faculty of Pharmacy Applied Science University. All experiments were carried out in accordance with the recommendations of the Research and Ethical Committee of the Faculty of Pharmacy at the Applied Science University. Mice were euthanized by cervical dislocation, and the spleen was removed aseptically. The cells of the spleen were passed through the mesh of a tissue grinder, and splenocytes suspension was prepared in RPMI-1640. The cell suspension was washed thrice for 10 min using RPMI1640 (2000r/min) and then resuspended in 5 ml of red blood cells lysis buffer. After 10 min, the cells were again centrifuged and resuspended in RPMI-1640. Splenocytes suspension was made (2 × 106 cells/ml) in RPMI– 1640 (supplemented with 50 U/ml penicillin, 50 U/ml streptomycin, 10% FBS) and the cells were seeded into different wells of 96 well culture plates. To this, 100 μL of different treatment was added. The plate was incubated for 48 h under 5% CO2 and humidified atmosphere of 90% air at 37°C.[27] After incubation, supernatants were collected to measure the concentration of interferon-gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-10 using Th1/Th2 ELISA kit (catalog # 88–7711–44; Affymetrix eBioscience, California, USA) following the procedure in the catalog.

 > Results and Discussion Top

The compound (L) is prepared by coupling of 4-bromo diazonium salt and acetylacetone in alkaline medium [Scheme 1].

The HL is characterized by several spectroscopic techniques and elemental analysis. The 1 H NMR signals taken in CDCl3 well supported the proposed structure of the compound (HL). The CH3 protons of acetylacetone part appear as sharp singlets at 2.60 and 2.46 ppm. The well-resolved aromatic protons appear as two doublets at 7.51 and 7.28 ppm [Figure 1].
Figure 1: 1H nuclear magnetic resonances in CDCl3 for compound L

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The characteristic hydrogen bonded broad singlet peak corresponds to O-H appears at 14.66 ppm. IR spectrum of ligand shows characteristic ν O-H at 3430 cm −1. The ν (C = O) of the ligand appears at 1664 cm −1 [Figure 2].
Figure 2: Infrared for for compound L

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The ligand may exist either in hydrazoketo (a) or in azoenol (b) form or may be in equilibrium [Scheme 2].

The experimental electronic spectra of the compound L in acetonitrile are shown in [Figure 3]. In 200–450 nm range the compound L exhibits two intense broad bands at 375 nm and 250 nm. The strong bands at 375 correspond to π→π* transition and the weak peak at 250 nm has n→π* transition.
Figure 3: Ultraviolet -visible for for compound L

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The antiproliferative activity of 3-(4-Bromo phenylazo)-2,4-pentanedione against MCF7, T47D and Vero cell lines were tested in vitro using the MTT assay. A dose-dependent inhibition was observed in all cell lines after treatment with increasing concentrations of 3-(4-Bromo phenylazo)-2,4-pentanedione [Figure 4]. The T47D cell line showed the highest sensitivity to 3-(4-Bromo phenylazo)-2,4-pentanedione treatment with >62% inhibition at 3-(4-Bromo phenylazo)-2,4-pentanedione concentration of 200 μM and an IC50 value of 82.5 μM [Table 1]. Other cell lines exhibited similar degrees of inhibition with increasing 3-(4-Bromo phenylazo)-2,4-pentanedione concentrations with higher resistance observed in MCF-7 cell line [Figure 4]. The IC50 values were 143.1 and 89.3 μM for MCF-7 and Vero cell lines, respectively [Table 1]. Our results are consistent with previous findings that reported the antiproliferative activity of other arylazo derivatives like 2-(arylazo) phenolate–palladium (II) which showed high activity to inhibit human lung, cervical, and ovarian cancer cell lines [28] and 4-[(3,5-diamino-1H-pyrazol-4-yl) diazenyl] phenol which exhibited selective inhibitory effect against colon adenocarcinoma.[29]
Figure 4: Effect of increasing concentrations of 3-(4-Bromo phenylazo)-2,4-pentanedione on the viability of Michigan Cancer Foundation-7, T47D and Vero cell lines. A dose-dependent inhibition was observed

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Table 1: The IC50 values (μM) of 3-(4-bromo phenylazo)-2,4-pentanedione on three cell lines (MCF7, T47D and Vero)

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Angiogenesis (blood vessels formation) is an essential step in cancer progression and development. To test whether or not the inhibition of angiogenesis has a role in the observed anticancer activity, the expression of VEGF was measured in vitro for each treatment [Figure 5]. Significant decrease in VEGF expression was observed in the cells treated with 42.5 μM 3-(4-Bromo phenylazo)-2,4-pentanedione with VEGF levels of 371 pg/ml. A higher degree of inhibition was observed in cells treated with 11 μM cisplatin with VEGF levels of 293 pg/ml in comparison with untreated control cells which exhibited high levels of VEGF (911 pg/ml). Although the degree of VEGF inhibition induced by 42.5 μM 3-(4-Bromo phenylazo)-2,4-pentanedione is lower than the inhibition induced by cisplatin, this result is promising and can help in explaining the anticancer effect of this compound.
Figure 5: The effect of different treatments on the expression of vascular endothelial growth factor. Concentration of vascular endothelial growth factor (pg/ml) in cells treated with 42.5 μM 3-(4-Bromo phenylazo)-2,4-pentanedione, 11 μM cisplatin, and untreated control cells. Each treatment was performed in triplicate. Results are expressed as means (bars) ± standard error of the mean (lines). The asterisks represent significant values

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To explore the effect of different treatments on the immune response of animals, levels of IFN-γ, IL-2, IL-4, and IL-10 were detected [Figure 6]. Results showed that the INF-γ level increased significantly when compared to the normal control. This increase was only significant in 3-(4-Bromo phenylazo)-2,4-pentanedione treated group. IL-2 levels also increased in 3-(4-Bromo phenylazo)-2,4-pentanedione treated group. Similar increase was also detected for IL-4. In contrast, IL-10 level was inhibited in group treated with 3-(4-Bromo phenylazo)-2,4-pentanedione compared with the control group. IFN-γ and IL-2 are signature cytokines of Th1 immune response while IL-4 is the cytokine dominating the Th2 immune response. Balanced ratio of Th1/Th2 cytokines was observed in healthy individuals and low levels of Th1 cytokines were detected in cancer patients.[30] It seems that 3-(4-Bromo phenylazo)-2,4-pentanedione can bind and stimulate the immune system mechanisms that limit the proliferation of cancer cells.
Figure 6: Effect of different treatments on serum levels of interferon gamma, interleukin-2, interleukin-4, and interleukin-10. Concentration of serum cytokines (pg/ml) in cells treated with 42.5 μM 3-(4-Bromo phenylazo)-2,4-pentanedione, 11 μM cisplatin and untreated control cells. Each treatment was performed in triplicate. Results are expressed as means (bars) ± standard error of the mean (lines). The asterisks represent significant values. The highest level of interferon gamma and interleukin-2 were detected in 3-(4-Bromo phenylazo)-2,4-pentanedione treatment

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The ability of 3-(4-Bromo phenylazo)-2,4-pentanedione to induce apoptosis was evaluated by measuring caspase-3 activation which is an important factor leading to apoptosis. We found that 3-(4-Bromo phenylazo)-2,4-pentanedione caused a significant increase in caspase-3 activation in MCF-7 cell line after incubating cells for 15, 24, and 48 h [Figure 7]. The activation of caspase-3 increased with increasing incubation time, and the peak activation of caspase-3 was achieved after 48 h incubation. These results proved that apoptosis induction is one of the mechanisms stimulated by 3-(4-Bromo phenylazo)-2,4-pentanedione to inhibit cancer cells proliferation.
Figure 7: Effect of 42.5 μM 3-(4-Bromo phenylazo)-2,4-pentanedione on the levels of caspase 3 activity at different incubation times. Each treatment was performed in triplicate. Results are expressed as means (bars) ± standard error of the mean (lines). The asterisks represent significant values

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 > Conclusion Top

3-(4-Bromo phenylazo)-2,4-pentanedione is a promising anticancer compound that targets cancer cells by angiogenesis inhibition and apoptosis induction. This compound deserves further testing to clearly understand its anticancer effects.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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