Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1286 2023-05-04 21:14:30 |
2 format correction -3 word(s) 1283 2023-05-05 03:57:21 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Rodrigues, J.D.F.; Philippsen, H.K.; Dolabela, M.F.; Nagamachi, C.Y.; Pieczarka, J.C. The Potential of DHA as Cancer Therapy Strategies. Encyclopedia. Available online: (accessed on 25 February 2024).
Rodrigues JDF, Philippsen HK, Dolabela MF, Nagamachi CY, Pieczarka JC. The Potential of DHA as Cancer Therapy Strategies. Encyclopedia. Available at: Accessed February 25, 2024.
Rodrigues, Jaqueline De Freitas, Hellen Kempfer Philippsen, Maria Fani Dolabela, Cleusa Yoshiko Nagamachi, Julio Cesar Pieczarka. "The Potential of DHA as Cancer Therapy Strategies" Encyclopedia, (accessed February 25, 2024).
Rodrigues, J.D.F., Philippsen, H.K., Dolabela, M.F., Nagamachi, C.Y., & Pieczarka, J.C. (2023, May 04). The Potential of DHA as Cancer Therapy Strategies. In Encyclopedia.
Rodrigues, Jaqueline De Freitas, et al. "The Potential of DHA as Cancer Therapy Strategies." Encyclopedia. Web. 04 May, 2023.
The Potential of DHA as Cancer Therapy Strategies

Docosahexaenoic acid (DHA), also known as omega-3 (n-3) polyunsaturated fatty acid (PUFA), is a natural compound that has demonstrated pharmacological activity against several malignant neoplasms. Available cancer treatments cause side effects, affect healthy cells, reduce the quality of life of patients and may cause resistance to antineoplastics. For these reasons, the search for new therapies is continuous.

fish oil anticancer molecules in vitro experiments

1. Introduction

Cancer is a pathology with a silent onset and is characterized by the uncontrolled anticipation of malignant cells [1]. This disease affects thousands of people worldwide, and the number of new cases and deaths is growing every year [2][3]. In 2018, there were 18.1 million new cases of cancer and 9.6 million deaths [4]. In 2020, the estimated number of new cases was 19.3 million, and there were 10 million deaths [5].
In 2020, the types of cancer with the highest global incidence, considering both sexes, were breast (11.7%), lung (11.4%), colorectal (10.0%), prostate (7.3%) and stomach (5.6%), and those with the highest mortality were lung (18%), colorectal (9.4%), liver (8.3%), stomach (7.7%) and breast (6.9%) [5].
Currently, the drugs epirubicin, oxaliplatin, fluorouracil, cisplatin and capecitabine are used in cancer therapy, but they have not been internationally standardized for this treatment [6][7]. One of the principles of chemotherapy is cytotoxicity, which is the ability to kill cancer cells; however, cytotoxicity often affects healthy cells and causes side effects, which reduces the quality of life of patients. In addition, cancer is susceptible to becoming resistant to drugs [8][9][10]. Thus, finding efficient therapies to combat cancer is of great interest [11].
Docosahexaenoic acid (DHA) is an omega-3 PUFA with lipophilic characteristics [12][13]. The disposition and amount of unsaturation in DHA favor more potent biological activity and less unsaturation compared to that of other fatty acids; thus, DHA is susceptible to oxidative stress processes [14][15]. DHA helps in the prevention of cardiovascular diseases [16] and premature retinopathy [17] and promotes anti-inflammatory action [18] and anticancer activity [10].
A few years ago, some fatty acids were evaluated in the treatment of cancer, with emphasis on DHA treatments that show the potential to inhibit uncontrolled cell proliferation [18], increase the cytotoxic capacity of antineoplastic agents and which do not interfere significantly in the quality of life of people [19]. In cells, the entry of fatty acids occurs by rapid diffusion and through the support of membrane proteins, such as fatty acid transport protein (FATP), fatty acid binding proteins (FABP) and fatty acid translocase (FAT), which are also responsible for PUFA metabolism and activity [20][21][22]. In cancer cells, the modulation of these membrane receptors is high, and with the acidic tumor microenvironment, the excessive internalization of lipids in the cell and consequent development of lipid droplets inside may occur [23][24]. The accumulation of DHA inside cells can cause irreversible oxidative stress, generating ferroptosis, which consists of a type of nonapoptotic cell death that causes tissue destruction due to the biological dysfunction of proteins and cell membranes [25][26].

2. Efficiency of DHA Against Different Types of Malignant Neoplasms

Anticancer activity was observed in studies involving cell lines that were treated with DHA alone, combined with other substances, including antineoplastics, and when molecules derived from DHA were used.
One recent study on the in vitro anticancer activity of DHA was in the field of nanomedicine. In vitro experiments with DHA were associated with TS and DOX drugs transported in nanostructured lipids (NLC-DHA-TS-DOX), resulting in strongly cytotoxic cell inhibition against breast cancer (4T1 cell line) [27]. The NLC-DHA nanoparticles did not show cytotoxic activity at the tested concentration. In this 4T1 lineage, DHA was also tested [28] with DHA at concentrations of 10, 20, 30, 40 and 50 µM, and the result also did not cause cytotoxicity. This cell line was also treated with PZ and PZ-DHA, and there was no cytotoxic effect [28]. Cytotoxicity results were obtained with this cell line at concentrations of 50, 100 and 150 µM DHA at 24 h and 48 h, but at concentrations of 10 and 25 µM, there was no cytotoxic effect [29]. However, they did not observe a statistically significant result of cell inhibition at concentrations of 10, 20 and 30 µM within 72 h of treatment with DHA [30]. The studies carried out by these authors differed in terms of the type of in vitro cell viability analysis assay, treatment time and, in some cases, the concentration used.
The SUM-149 cell line was tested with DHA, PZ and PZ-DHA [30]. Statistically significant cytotoxic activity was observed after treatment with DHA and PZ-DHA at concentrations of 30, 40 and 50 µM. This cytotoxic effect was not observed by the same authors when SUM-149 cells were treated with PZ. This result demonstrates that the type of drug tested interferes with the cell inhibition effect [30]. This can also be observed on MDA-MB-231 cells within 24 h with the drug 13R,20-diHDHA, and the study did not obtain statistically significant results at any of the tested concentrations [31]. A noncytotoxic result was also observed regarding the 4-OXO-DHA molecule [32].
Studies with other DHA-derived molecules were also performed [32]. The substance 4-OH-DHA was analyzed within 96 h at a concentration of 100 µM and showed cytotoxicity in the cell lines MCF-10F, trMCF, bsMCF, MDA-MB-231 and SK-BR-3, with the exception of cytotoxic activity in the tested cell line T-47D. When the same authors tested the substance 4-OXO-DHA, they obtained a statistically significant cytotoxicity result in all these lineages [32]. The PZ-DHA ester substance was toxic to liver cancer but not to the HP-F and RTCP10 lineages [33].
The concentration of 100 µM DHA demonstrated a cytotoxic effect in breast tumor and nontumor cell lines. This concentration was also toxic to lung [17], colorectal [20][27], prostate [19], stomach [18] and liver cell lines [33]. However, in the normal cell lines of the stomach (GES-1) [18] and liver (HP-F and RTCP10) [33], there was no statistically significant cytotoxic activity.
Cytotoxic analysis of DHA was tested comparatively with other fatty acids. In comparison with omega 3 EPA, the cytotoxic effect was shown by both substances in colorectal [34], prostate [35] and liver [33] cancer cell lines. In comparison with omega 3 (ALA), in the liver cancer cell line, only DHA was cytotoxic [33]. In comparison with omega 6 (LA), both in the colorectal cancer cell line and in the liver cancer cell line, only DHA showed cytotoxic activity that was considered statistically significant. In comparison with omega 6 (AA), in the prostate cancer cell lines, only DH was cytotoxic. In comparison with omega 9 (OA), in the liver cancer cell line, only DHA was cytotoxic. These analyses corroborate with other information, which mentioned that the disposition and quantity of unsaturation in DHA interferes with the biological activity of fatty acids [14][15].
In other studies, the cytotoxic activity of DHA alone or associated with other substances was observed. A comparison was made between DHA alone, apatinib alone and the two substances in combination [28]. The results showed that the combination of the two substances showed a synergistic effect against breast cancer. The synergistic effect was also observed in the association of nanocarried DHA with TS and DOXO in breast cancer [27], in the association of DHA with PunA in colorectal cancer [20] and with ISL in colorectal cancer [26].
The administration of DHA in cancer patients has been shown to be a coadjuvant in chemotherapy treatment. The addition of DHA in the diet, either in supplementation associated with EPA and/or proteins, helped in the process of muscle mass gain, weight maintenance, tolerance to chemotherapy and tumor shrinkage [36][37][38]. The intake of 6 g of protein, 1.1 g of EPA and 0.5 g of DHA per day is recommended to increase lean mass gain [38], and the minimum dose of 2.0 g/day of EPA + DHA can be used in clinical trials and is sufficient for tissue enrichment to occur [36].
Thus, DHA exhibits cytotoxic action against different tumor lineages and can be ingested in the diet as an adjunct to cancer treatment, within the specific concentrations presented for each type of cancer. In children, these dosages may vary to lower dosage; however, further research on the use of this drug is still needed to standardize the protocol for use in different cancer lineages.


  1. Wang, J.-J.; Lei, K.-F.; Han, F. Tumor Microenvironment: Recent Advances in Various Cancer Treatments. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3855–3864.
  2. Instituto Nacional de Câncer José Alencar Gomes da Silva. Estimativa 2018: Incidência de Câncer No Brasil; INCA: Rio de Janeiro, Brasil, 2017.
  3. Instituto Nacional de Câncer José Alencar Gomes da Silva. Estimativa 2020: Incidência de Câncer No Brasil; INCA: Rio de Janeiro, Brasil, 2019.
  4. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2018, 68, 394–424.
  5. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  6. Li, K.; Zhang, A.; Li, X.; Zhang, H.; Zhao, L. Advances in clinical immunotherapy for gastric cancer. Biochim. Biophys. Acta BBA Rev. Cancer 2021, 1876, 188615.
  7. Bilici, A. Treatment options in patients with metastatic gastric cancer: Current status and future perspectives. World J. Gastroenterol. 2014, 20, 3905–3915.
  8. Sitarz, R.; Skierucha, M.; Mielko, J.; Offerhaus, J.; Maciejewski, R.; Polkowski, W. Gastric cancer: Epidemiology, prevention, classification, and treatment. Cancer Manag. Res. 2018, 10, 239–248.
  9. Fu, B.; Wang, N.; Tan, H.-Y.; Li, S.; Cheung, F.; Feng, Y. Multi-Component Herbal Products in the Prevention and Treatment of Chemotherapy-Associated Toxicity and Side Effects: A Review on Experimental and Clinical Evidences. Front. Pharmacol. 2018, 9, 1394.
  10. Nurgali, K.; Jagoe, R.T.; Abalo, R. Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? Front. Pharmacol. 2018, 9, 245.
  11. Pizato, N.; Luzete, B.C.; Kiffer, L.F.M.V.; Corrêa, L.H.; De Oliveira Santos, I.; Assumpção, J.A.F.; Ito, M.K.; Magalhães, K.G. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells. Sci. Rep. 2018, 8, 1952.
  12. Aslan, C.; Maralbashi, S.; Kahroba, H.; Asadi, M.; Soltani-Zangbar, M.S.; Javadian, M.; Shanehbandi, D.; Baradaran, B.; Darabi, M.; Kazemi, T. Docosahexaenoic acid (DHA) inhibits pro-angiogenic effects of breast cancer cells via down-regulating cellular and exosomal expression of angiogenic genes and microRNAs. Life Sci. 2020, 258, 118094.
  13. Bae, S.; Kim, M.-K.; Kim, H.S.; Moon, Y.-A. Arachidonic acid induces ER stress and apoptosis in HT-29 human colon cancer cells. Anim. Cells Syst. 2020, 24, 260–266.
  14. Dierge, E.; Debock, E.; Guilbaud, C.; Corbet, C.; Mignolet, E.; Mignard, L.; Bastien, E.; Dessy, C.; Larondelle, Y.; Feron, O. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 2021, 33, 1701–1715.e5.
  15. Patterson, E.; Wall, R.; Fitzgerald, G.F.; Ross, R.; Stanton, C. Health Implications of High Dietary Omega-6 Polyunsaturated Fatty Acids. J. Nutr. Metab. 2012, 2012, 539426.
  16. Tasaki, S.; Horiguchi, A.; Asano, T.; Ito, K.; Asano, T.; Asakura, H. Docosahexaenoic acid inhibits the phosphorylation of STAT3 and the growth and invasion of renal cancer cells. Exp. Ther. Med. 2017, 14, 1146–1152.
  17. Bai, X.; Shao, J.; Zhou, S.; Zhao, Z.; Li, F.; Xiang, R.; Zhao, A.Z.; Pan, J. Inhibition of lung cancer growth and metastasis by DHA and its metabolite, RvD1, through miR-138-5p/FOXC1 pathway. J. Exp. Clin. Cancer Res. 2019, 38, 479.
  18. Ortega, L.; Lobos-González, L.; Reyna-Jeldes, M.; Cerda, D.; De la Fuente-Ortega, E.; Castro, P.; Bernal, G.; Coddou, C. The Ω-3 fatty acid docosahexaenoic acid selectively induces apoptosis in tumor-derived cells and suppress tumor growth in gastric cancer. Eur. J. Pharmacol. 2021, 896, 173910.
  19. Shao, Z.C.; Zhu, B.H.; Huang, A.F.; Su, M.Q.; An, L.J.; Wu, Z.P.; Jiang, Y.J.; Guo, H.; Han, X.-Q.; Liu, C.-M.; et al. Original Article Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells (docosahexaenoic acid/drug resistance/ferroptosis/GPX4/autophagy/prostate). Folia Biol. 2022, 68, 59–71.
  20. Vermonden, P.; Vancoppenolle, M.; Dierge, E.; Mignolet, E.; Cuvelier, G.; Knoops, B.; Page, M.; Debier, C.; Feron, O.; Larondelle, Y. Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells. Nutrients 2021, 13, 2751.
  21. Khalid, W.; Gill, P.; Arshad, M.S.; Ali, A.; Ranjha, M.M.A.N.; Mukhtar, S.; Afzal, F.; Maqbool, Z. Functional behavior of DHA and EPA in the formation of babies brain at different stages of age, and protect from different brain-related diseases. Int. J. Food Prop. 2022, 25, 1021–1044.
  22. Ghasemifard, S.; Hermon, K.; Turchini, G.M.; Sinclair, A.J. Metabolic fate (absorption,β-oxidation and deposition) of long-chainn-3 fatty acids is affected by sex and by the oil source (krill oil or fish oil) in the rat. Br. J. Nutr. 2015, 114, 684–692.
  23. Lv, W.; Xu, D. Docosahexaenoic Acid Delivery Systems, Bioavailability, Functionality, and Applications: A Review. Foods 2022, 11, 2685.
  24. Wood, E.H.; Harper, C.A. Lipid supplement reduced ROP in premature infants. J. Pediatr. 2021, 234, 286–288.
  25. Park, M.; Lim, J.W.; Kim, H. Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-κB. Nutrients 2018, 10, 1621.
  26. Jin, H.; Kim, H.S.; Yu, S.T.; Shin, S.R.; Lee, S.H.; Seo, G.S. Synergistic anticancer effect of docosahexaenoic acid and isoliquiritigenin on human colorectal cancer cells through ROS-mediated regulation of the JNK and cytochrome c release. Mol. Biol. Rep. 2021, 48, 1171–1180.
  27. Lages, E.B.; Fernandes, R.S.; Silva, J.D.O.; de Souza, M.; Cassali, G.D.; de Barros, A.L.B.; Ferreira, L.A.M. Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity. Biomed. Pharmacother. 2020, 132, 110876.
  28. Ma, Y.; Yu, J.; Li, Q.; Su, Q.; Cao, B. Addition of docosahexaenoic acid synergistically enhances the efficacy of apatinib for triple-negative breast cancer therapy. Biosci. Biotechnol. Biochem. 2020, 84, 743–756.
  29. Zhang, J.; Xue, B.; Du, C.; Zhang, L.; Wang, Y.; Zhang, Y.; Li, J. Docosahexaenoic acid supresses breast cancer cell proliferation and migration by promoting the expression of miR-99a and targeting mTOR signaling. Arab. J. Chem. 2021, 14, 103298.
  30. Fernando, W.; Coyle, K.; Marcato, P.; Rupasinghe, H.V.; Hoskin, D.W. Phloridzin docosahexaenoate, a novel fatty acid ester of a plant polyphenol, inhibits mammary carcinoma cell metastasis. Cancer Lett. 2019, 465, 68–81.
  31. Wang, L.; Choi, H.S.; Lee, B.; Choi, J.H.; Jang, Y.-S.; Seo, J.-W. 13R,20-Dihydroxydocosahexaenoic Acid, a Novel Dihydroxy- DHA Derivative, Inhibits Breast Cancer Stemness through Regulation of the Stat3/IL-6 Signaling Pathway by Inducing ROS Production. Antioxidants 2021, 10, 457.
  32. Pogash, T.J.; El-Bayoumy, K.; Amin, S.; Gowda, K.; De Cicco, R.L.; Barton, M.; Su, Y.; Russo, I.H.; Himmelberger, J.A.; Slifker, M.; et al. Oxidized derivative of docosahexaenoic acid preferentially inhibit cell proliferation in triple negative over luminal breast cancer cells. Vitr. Cell. Dev. Biol. Anim. 2019, 51, 121–127.
  33. Nair, S.V.G.; Ziaullah; Rupasinghe, H.P.V. Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression. PLoS ONE 2014, 9, e107149.
  34. Kato, T.; Kolenic, N.; Pardini, R.S. Docosahexaenoic Acid (DHA), a Primary Tumor Suppressive Omega-3 Fatty Acid, Inhibits Growth of Colorectal Cancer Independent of p53 Mutational Status. Nutr. Cancer 2007, 58, 178–187.
  35. Sun, Y.; Jia, X.; Hou, L.; Liu, X.; Gao, Q. Involvement of apoptotic pathways in docosahexaenoic acid-induced benefit in prostate cancer: Pathway-focused gene expression analysis using RT2 Profile PCR Array System. Lipids Health Dis. 2017, 16, 59.
  36. Fasano, E.; Serini, S.; Cittadini, A.; Calviello, G. Long-chain n-3 PUFA against breast and prostate cancer: Which are the appropriate doses for intervention studies in animals and humans? Crit. Rev. Food Sci. Nutr. 2017, 57, 2245–2262.
  37. Mocellin, M.C.; Silva, J.D.A.P.E.; Camargo, C.; Fabre, M.E.D.S.; Gevaerd, S.; Naliwaiko, K.; Moreno, Y.M.F.; Nunes, E.; Trindade, E.B.S.D.M. Fish Oil Decreases C-Reactive Protein/Albumin Ratio Improving Nutritional Prognosis and Plasma Fatty Acid Profile in Colorectal Cancer Patients. Lipids 2013, 48, 879–888.
  38. Shirai, Y.; Okugawa, Y.; Hishida, A.; Ogawa, A.; Okamoto, K.; Shintani, M.; Morimoto, Y.; Nishikawa, R.; Yokoe, T.; Tanaka, K.; et al. Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia. Sci. Rep. 2017, 7, 4826.
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , ,
View Times: 372
Revisions: 2 times (View History)
Update Date: 05 May 2023