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[10]-Gingerol improves doxorubicin anticancer activity and decreases its side effects in triple negative breast cancer models

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Abstract

Purpose

Although doxorubicin is widely used to treat cancer, severe side effects limit its clinical use. Combination of standard chemotherapy with natural products can increase the efficacy and attenuate the side effects of current therapies. Here we studied the anticancer effects of a combined regimen comprising doxorubicin and [10]-gingerol against triple-negative breast cancer, which does not respond to hormonal or targeted therapies.

Methods

Cytotoxicity was evaluated by MTT assay, cell cycle progression and apoptosis were analyzed by flow cytometry and signaling pathways were analyzed by Western blotting in human and murine triple negative breast cancer cell systems. The anticancer/antimetastatic and toxic effects of the combined regimen was evaluated using syngeneic and xenograft orthotopic models.

Results

The combination of doxorubicin and [10]-gingerol significantly increased the number of apoptotic cells, compared to each compound alone. In 4T1Br4 cells, the combined regimen was the only condition able to increase the levels of active caspase 3 and γH2AX and to decrease the level of Cdk-6 cyclin. In vivo, doxorubicin (3 mg/Kg, D3) and [10]-gingerol (10 mg/Kg, G10) resulted in a significant reduction in the volume of primary tumors and a decrease in the number of circulating tumor cells (CTCs). Interestingly, only the combined regimen led to decreased tumor burdens to distant organs (i.e., metastasis) and reduced chemotherapy-induced weight loss and hepatotoxicity in tumor-bearing animals. Likewise, in a xenograft model, only the combined regimen was effective in significantly reducing the primary tumor volume and the prevalence of CTCs.

Conclusions

Our data indicate that [10]-gingerol has potential to be used as a neoadjuvant or in combined therapy with doxorubicin, to improve its anticancer activity.

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Acknowledgements

We would like to thank Dr. Normand Pouliot and Dr. Richard Redvers from ONJCRI, Melbourne, Australia for providing the 4T1Br4 and MDA-MB-231 HTML.6 cells lines used in this work. This work was supported by the Sao Paulo Research Foundation (FAPESP grant numbers 2015/24940-8 and 2013/00760-3), the National Council for Scientific and Technological Development (CNPq grant number 401506/2016-9) and the Coordinating Support for Higher Education (CAPES grant number 001). ACBMM has a post-doctoral fellowship from FAPESP (2016/23202-6), RT had a post-doctoral fellowship from CNPq (403568/2015-3) B. Annabi holds a research Chair in Cancer Prevention and Treatment at UQAM.

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  1. Rebeka Tomasin

    Present address: E-signal Lab, Biochemistry Department, Institute of Chemistry, São Paulo University, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil

  2. Ana Carolina Baptista Moreno Martin and Rebeka Tomasin contributed equally to this work.

Authors and Affiliations

  1. Department of Gerontology, Federal University of São Carlos, Rodovia Washington Luís, Km 235, São Carlos, SP, 13565-905, Brazil

    Ana Carolina Baptista Moreno Martin, Rebeka Tomasin, Liany Luna-Dulcey, Angélica Elen Graminha, Marina Araújo Naves, Ramon Handerson Gomes Teles & Márcia Regina Cominetti

  2. Department of Pathology, Barretos Cancer Hospital, R. Antenor Duarte Vilela, 1331 - Dr. Paulo Prata, Barretos, SP, 14784-4003, Brazil

    Vinicius Duval da Silva

  3. Departament of Pharmacology, Federal University of Sergipe, Av. Gov. Marcelo Déda, 13, CEP 49400-000, Lagarto, SE, Brazil

    James Almada da Silva

  4. School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, 14040-903, Ribeirao Preto, SP, Brazil

    Paulo Cezar Vieira

  5. Department of Chemistry, Université du Québec à Montréal, Succursale Centre-ville, Case postale 8888, Montréal, Québec, H3C 3P8, Canada

    Borhane Annabi

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Contributions

ACBM Martin and R Tomasin: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, final approval of the version to be submitted. L Luna-Dulcey, AE Graminha, MA Naves, RAG Teles, VD Silva, JA Silva, PC Vieira and B Annabi: analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, final approval of the version to be submitted. MR Cominetti: funding acquisition, project administration, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, final approval of the version to be submitted.

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Correspondence to Ana Carolina Baptista Moreno Martin.

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Supplementary Fig. 1

IC50 curves and values for doxorubicin and [10]-gingerol in different cell lines after 72 h of treatment. aPublished by Martin et al. (2017) [22]. (PNG 4550 kb)

High Resolution Image (TIF 18199 kb)

Supplementary Fig. 2

Representative cell cycle plots of (A) 4T1Br4 and (B) MDA-MB-231 HMTL.6 cells of each indicated treatment. (PNG 3192 kb)

High Resolution Image (TIF 12770 kb)

Supplementary Fig. 3

Representative dot plots from apoptosis assay in (A) 4T1Br and in (B) MDA-MB-231 HMTL.6 of each indicated treatment. Total apoptosis was evaluated from the sum of early and late apoptosis in (C) 4T1Br4 and (D) MDA-MB-231 HMTL.6 cell lines. Data are presented as mean±SEM. One-way ANOVA followed by Bonferroni’s post-test, *p<0.0001. (PNG 5237 kb)

High Resolution Image (TIF 20950 kb)

Supplementary Fig. 4

Western blotting quantifications and representative membranes for Cdk-1, 2, 4 and 6, pro-caspase-3, active caspase-3 and γ-H2AX of each indicated treatment in (A) 4T1Br4. Representative membranes for endogenous control β-actin for (B) cell cycle proteins and (C) cell death and DNA damage. Western blotting quantifications and representative membranes for Cdk-1, 2, 4 and 6, pro-caspase-3, active caspase-3 and γ-H2AX in (D) MDA-MB-231 HMTL.6. Representative membranes for endogenous control β-actin for (E) cell cycle proteins and (F) cell death and DNA damage. The treatments in the western blotting membranes are in the following order: Lane 1: precision plus protein kaleidoscope (10–250 kDa), lane 2: Control, lane 3: G50, lane 4: D50, lane 5: G50D50, lane 6: G30D20, lane 7: G20D30. Data are presented as mean± SEM. One-way ANOVA followed by Dunnet’s post-test, ***p<0.0001, **p<0.001 and *p<0.01. (PNG 4011 kb)

High Resolution Image (TIF 16046 kb)

Supplementary Fig. 5

Orthotopic syngeneic metastasis model (n = 15–16 in each group). (A) Spleen and (B) lung weight collected at the endpoint (28 days after IMFP injection) from syngeneic orthotopic experiments of each indicated treatment. Data are presented as mean±SEM. One-way ANOVA followed by Dunnett’s post-test, **p<0.0001. (PNG 1310 kb)

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Supplementary Table 1

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Baptista Moreno Martin, A.C., Tomasin, R., Luna-Dulcey, L. et al. [10]-Gingerol improves doxorubicin anticancer activity and decreases its side effects in triple negative breast cancer models. Cell Oncol. 43, 915–929 (2020). https://doi.org/10.1007/s13402-020-00539-z

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  • DOI: https://doi.org/10.1007/s13402-020-00539-z

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