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. 2021 May 28;26(11):3241.
doi: 10.3390/molecules26113241.

Anacardic Acids from Amphipterygium adstringens Confer Cytoprotection against 5-Fluorouracil and Carboplatin Induced Blood Cell Toxicity While Increasing Antitumoral Activity and Survival in an Animal Model of Breast Cancer

Jairo Galot-Linaldi  1 , Karla M Hernández-Sánchez  2 , Elizabet Estrada-Muñiz  1 , Libia Vega  1
Affiliations

Anacardic Acids from Amphipterygium adstringens Confer Cytoprotection against 5-Fluorouracil and Carboplatin Induced Blood Cell Toxicity While Increasing Antitumoral Activity and Survival in an Animal Model of Breast Cancer

Jairo Galot-Linaldi et al. Molecules. .

Abstract

Amphipterygium adstringens (cuachalalate) contains anacardic acids (AAs) such as 6-pentadecyl salicylic acid (6SA) that show immunomodulatory and antitumor activity with minimal or no secondary adverse effects. By contrast, most chemotherapeutic agents, such as 5-fluorouracil (5-FU) and carboplatin (CbPt), induce myelosuppression and leukopenia. Here, we investigated the myeloprotective and antineoplastic potential of an AA extract or the 6SA as monotherapy or in combination with commonly used chemotherapeutic agents (5-FU and CbPt) to determine the cytoprotective action of 6SA on immune cells. Treatment of Balb/c breast tumor-bearing female mice with an AA mixture or 6SA did not induce the myelosuppression or leukopenia observed with 5-FU and CbPt. The co-administration of AA mixture or isolated 6SA with 5-FU or CbPt reduced the apoptosis of circulating blood cells and bone marrow cells. Treatment of 4T1 breast tumor-bearing mice with the AA mixture or 6SA reduced tumor growth and lung metastasis and increased the survival rate compared with monotherapies. An increased effect was observed in tumor reduction with the combination of 6SA and CbPt. In conclusion, AAs have important myeloprotective and antineoplastic effects, and they can improve the efficiency of chemotherapeutics, thereby protecting the organism against the toxic effects of drugs such as 5-FU and CbPt.

Keywords: Amphiterygium adstringens; anacardic acids; antineoplastic agent; autologous tumor model; myeloprotective.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of 6-pentadecyl salicylic acid (6SA).
Figure 2
Figure 2
AA mixture characterization. Thin layer chromatography of 6SA (REF), fraction 68 of the AA mixture (F68), and the complete hexane extract from the bark of A. adstringens (EXT) by short wavelength ultraviolet light and cerium molybdate stain (A). 1H NMR spectrum (600 MHz, CDCl3) of fraction 68 (B): δ 7.25 (t, 1H, J = 7.25 Hz, H-5), 6.92 (dd, 1H, J = 7.62, 4.01 Hz, H-6), 6.48 (dd, 1H, J = 7.1, 3.8 Hz, H-4), 2.82 (m, 2H, H-8), 1.6 (m, 2H, H-9), 1.28 (m, 26H, H-10-21), 0.89 (t, 3H, J = 6.95, 6.95 Hz, H-22).
Figure 3
Figure 3
Anacardic acids mixture and 6SA decrease leukopenia and myelosuppression caused by 5-FU and CbPt. Mice were injected with 4T1 cells (5 × 103 in 50 μL), and 8 days after tumor implantation, they received 6SA (6 mg/kg), AA (6 mg/kg), 5-FU (40 mg/kg), CbPt (100 mg/kg), 6SA/5-FU (6 + 40 mg/kg), AA/5-FU (6 + 40 mg/kg), or 6SA/CbPt (6 + 100 mg/kg) for 21 days. Flow cytometry of annexin V and propidium iodide stained (A) blood (B) or bone marrow cells (C). Mean ± SD, n = 6. * p < 0.05 One-Way ANOVA post hoc Bonferroni vs. control, a vs. 5-FU, b vs. CbPt, c vs. 6SA, or d vs. AA.
Figure 4
Figure 4
Anacardic acids inhibit tumor growth, decrease lung metastasis, and increase animal survival. Mice were injected with 4T1 cells (5 × 103 in 50 μL), and 8 days after tumor implantation, they received 6SA (6 mg/kg), AA (6 mg/kg), 5-FU (40 mg/kg), CbPt (100 mg/kg), 6SA/5-FU (6 + 40 mg/kg), AA/5-FU (6 + 40 mg/kg), or 6SA/CbPt (6 + 100 mg/kg) for 21 days. Excised tumors after 21 days of treatments (A), tumor volume (B,C), and tumor weight (D). Metastatic assay of 4T1 cells (E) and the percentage of 4T1 colony cells in lung tissue (F). Survival rate of animals after treatments (G). Mean ± SEM (B,C), Mean ± SD (D,F), n = 6. a 5-FU, b CbPt, c 6SA, d AA, # 6SA/5-FU, & AA/5-FU, and λ 6SA/CbPt p < 0.05 Two-Way ANOVA post hoc Bonferroni vs. control, * p < 0.05 One-Way ANOVA post hoc Bonferroni vs. control, a vs. 5-FU, b vs. CbPt, and d vs AA. α p < 0.05 Two-Way ANOVA post hoc Bonferroni CbPt vs. 6SA/CbPt.
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