Kwas Karnozynowy w Nowotworzeniu: od Teorii do Praktyki

Magdalena Wojtczuk; Agnieszka Dominiak

doi:10.56782/pps.329

Published : 2025-02-27

Vol. 23 No. 1 (2025)

Carnosic Acid in Carcinogenesis: From Theory to Practice

Magdalena Wojtczuk

Agnieszka Dominiak

DOI: https://doi.org/10.56782/pps.329

Abstract

In light of the steadily increasing number of cancer diagnoses, there is a growing urgency to identify effective methods for prevention and anti-cancer therapy. Notably, approximately 50% of all clinical drugs are derived from natural sources, thus phytochemicals emerging as a promising options. One such candidate is carnosic acid, a phenolic diterpenoid compound richly found in rosemary (Rosmarinus officinalis L.). Over the past decade, there has been a significant increase in the number of in vitro and in vivo studies on the biological activities of carnosic acid and its derivatives. Carnosic acid has been shown to enhance antioxidatant defense, inhibit the activity of proteolytic enzymes, block epithelial-mesenchymal transition and reduce cell adhesion and migration, as well as prevent tumor invasion and metastasis. Finally, it promotes tumor cell death through apoptosis and autophagy. Its effectiveness as a chemopreventive, antiproliferative, and anti-invasive agent on human cell lines and syngeneic cancer models, coupled with its synergistic effects when used in combination with chemotherapeutic drugs, low cost, and relatively simple acquisition, underscores the potential of carnosic acid in cancer treatment. However, despite promising preclinical findings, clinical validation is still lacking. Several areas remain to be explored, such as the pharmacokinetics of CA in the human body, the need for dosage adjustments, and safe exposure durations. Before carnosic acid can be used in patients, a comprehensive safety assessment is essential, the individual metabolic profiles should be taken into account. While carnosic acid-containing functional foods seem to be a promising strategy to reduce the global cancer burden, clinical trials using carnosic acid in oncology are still fully justified.

Keywords:

anticancer activity, cancer, carnosic acid, phytotherapy

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Wojtczuk, M., & Dominiak, A. (2025). Carnosic Acid in Carcinogenesis: From Theory to Practice. Prospects in Pharmaceutical Sciences, 23(1), 80–88. https://doi.org/10.56782/pps.329

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References

1. Giovannucci, E. Nutritional epidemiology and cancer: A Tale of Two Cities. Cancer Causes Control 2018, 29 (11), 1007-1014. DOI: 10.1007/s10552-018-1088-y

2. Blot, W. J.; Tarone, R. E. Doll and Peto's quantitative estimates of cancer risks: holding generally true for 35 years. J. Natl. Cancer Inst. 2015, 107(4), Art. No: djv044. DOI: 10.1093/jnci/djv044

3. Zhang, Y. J.; Gan, R. Y.; Li, S.; Zhou, Y.; Li, A. N.; Xu, D. P.; Li, H. B. Antioxidant Phytochemicals for the Prevention and Treatment of Chronic Diseases. Molecules 2015, 20(12), 21138-21156. DOI: 10.3390/‌‌‌‌‌‌‌molecules‌‌‌‌201219753

4. Galasko, D. R.; Peskind, E.; Clark, C. M.; Quinn, J. F.; Ringman, J. M.; Jicha, G. A.; Cotman, C.; Cottrell, B.; Montine, T. J.; Thomas, R. G.; Aisen, P. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch. Neurol. 2012, 69 (7), 836-841. DOI: 10.1001/archneurol.2012.85

5. Tanaka, S.; Haruma, K.; Yoshihara, M.; Kajiyama, G.; Kira, K.; Amagase, H.; Chayama, K. Aged garlic extract has potential suppressive effect on colorectal adenomas in humans. J. Nutr. 2006, 136(3 Suppl), 821-826. DOI: 10.1093/jn/136.3.821S

6. El Oirdi, M. Harnessing the Power of Polyphenols: A New Frontier in Disease Prevention and Therapy. Pharmaceuticals (Basel) 2024, 17(6). DOI: 10.3390/ph17060692

7. Moreno, S.; Scheyer, T.; Romano, C. S.; Vojnov, A. A. Antioxidant and antimicrobial activities of rosemary extracts linked to their polyphenol composition. Free Radic. Res. 2006, 40(2), 223-231. DOI: 10.1080/‌10715760500473834

8. Moore, J.; Yousef, M.; Tsiani, E. Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols. Nutrients 2016, 8(11), Art. No: 731. DOI: 10.3390/nu8110731

9. Chen, X.; Wei, C.; Zhao, J.; Zhou, D.; Wang, Y.; Zhang, S.; Zuo, H.; Dong, J.; Zhao, Z.; Hao, M.; et al. Carnosic acid: an effective phenolic diterpenoid for prevention and management of cancers via targeting multiple signaling pathways. Pharmacol. Res. 2024, 206, Art. No: 107288. DOI: 10.1016/j.phrs.2024.107288

10. Birtić, S.; Dussort, P.; Pierre, F. X.; Bily, A. C.; Roller, M. Carnosic acid. Phytochemistry 2015, 115, 9-19. DOI: 10.1016/j.phytochem.2014.12.026

11. Petiwala, S. M.; Johnson, J. J. Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity. Cancer Lett. 2015, 367 (2), 93-102. DOI: 10.1016/j.canlet.2015.07.005

12. Younes, M.; Aggett, P.; Aguilar, F.; Crebelli, R.; Dusemund, B.; Filipič, M.; Frutos, M. J.; Galtier, P.; Gott, D.; Gundert-Remy, U.; et al. Refined exposure assessment of extracts of rosemary (E 392) from its use as food additive. EFSA J. 2018, 16. Art. No: 5373. DOI: 10.2903/j.efsa.2018.5373

13. Sirajudeen, F.; Bou Malhab, L.J.; Bustanji, Y.; Shahwan, M.; Alzoubi, K. H.; Semreen, M. H.; Taneera, J.; El-Huneidi, W.; Abu-Gharbieh, E. Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives. Biomol. Ther. (Seoul) 2024, 32 (1), 38-55. DOI: 10.4062/biomolther.2023.054

14. Zuo H.X. Studies on the Pharmacokinetics and Metabolism of Carnosic Acid in Rats, dissertation, Shenyang Pharmaceutical University, 2008.

15. de Oliveira, M. R. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol. Neurobiol. 2016, 53 (9), 6155-6168. DOI: 10.1007/s12035-015-9519-1

16. Rasoolijazi, H.; Azad, N.; Joghataei, M. T.; Kerdari, M.; Nikbakht, F.; Soleimani, M. The protective role of carnosic acid against beta-amyloid toxicity in rats. Sci. World J. 2013, Art. No: 917082. DOI: 10.1155/2013/917082

17. Doolaege, E. H.; Raes, K.; De Vos, F.; Verhé, R.; De Smet, S. Absorption, distribution and elimination of carnosic acid, a natural antioxidant from Rosmarinus officinalis, in rats. Plant Food Hum. Nutr. 2011, 66 (2), 196-202. DOI: 10.1007/s11130-011-0233-5

18. Yan, H.; Wang, L.; Li, X.; Yu, C.; Zhang, K.; Jiang, Y.; Wu, L.; Lu, W.; Tu, P. High-performance liquid chromatography method for determination of carnosic acid in rat plasma and its application to pharmacokinetic study. Biomed. Chromatogr. 2009, 23(7), 776-781. DOI: 10.1002/bmc.1184

19. Schwarz, K.; Ternes, W. Antioxidative constituents of Rosmarinus officinalis and Salvia officinalis. II. Isolation of carnosic acid and formation of other phenolic diterpenes. Z. Lebensm. Unters. Forsch. 1992, 195 (2), 99-103. DOI: 10.1007/bf01201766

20. Buchin, Y.; Sakemi, Y.; Hamashima, R.; Morioka, Y.; Yamanaka, D.; Hakuno, F.; Takahashi, S.-i.; Shindo, K. Structures and biological activities of new carnosic acid- and carnosol-related compounds generated by heat treatment of rosemary. Phytochem. Lett. 2019, 30, 43-48. DOI: 10.1016/j.phytol.2019.01.005

21. da Silva, S. B.; Amorim, M.; Fonte, P.; Madureira, R.; Ferreira, D.; Pintado, M.; Sarmento, B. Natural extracts into chitosan nanocarriers for rosmarinic acid drug delivery. Pharm. Biol. 2015, 53 (5), 642-652. DOI: 10.3109/13880209.2014.935949

22. Wang, J.; Li, G.; Rui, T.; Kang, A.; Li, G.-C.; Fu, T.; Li, J.; Di, L.; Cai, B. Pharmacokinetics of rosmarinic acid in rats by LC-MS/MS: absolute bioavailability and dose proportionality. RSC Adv. 2017, 7, 9057-9063. DOI: 10.1039/C6RA28237G.

23. Garti, N.; McClements, D. J. Encapsulation technologies and delivery systems for food ingredients and nutraceuticals, Woodhead Publishing: Oxford, 2012. 612, 2012; 450-470.

24. Zheng, H.; Wijaya, W.; Zhang, H.; Feng, K.; Liu, Q.; Zheng, T.; Yin, Z.; Cao, Y.; Huang, Q. Improving the bioaccessibility and bioavailability of carnosic acid using a lecithin-based nanoemulsion: complementary in vitro and in vivo studies. FOOD FUNCT. 2020, 11 (9), 8141-8149. DOI: 10.1039/d0fo01098g

25. Luis, J. C.; Johnson, C. B. Seasonal variations of rosmarinic and carnosic acids in rosemary extracts. Analysis of their in vitro antiradical activity. Span. J. Agric. Res. 2005, 3, Art. No: 106. DOI: 10.5424/sjar/2005031-130.

26. Habtemariam, S. Anti-Inflammatory Therapeutic Mechanisms of Natural Products: Insight from Rosemary Diterpenes, Carnosic Acid and Carnosol. Biomedicines 2023, 11 (2). Art. No: 545. DOI: 10.3390/biomedicines11020545

27. Shrivastava, S.; Bahuguna, T.; Mondal, S.; Kumar, S.; Mathew, B.; Jeengar, M. K.; Naidu, V. G. M. Attenuation of adjuvant-induced arthritis with carnosic acid by inhibiting mPGES-1, COX-2, and bone loss in male SD rats. Immunopharmacol. Immunotoxicol. 2024, 46 (4), 538-549. DOI: 10.1080/08923973.2024.2377984

28. Chen, Y.; Wang, Y.; Qin, Q.; Zhang, Y.; Xie, L.; Xiao, J.; Cao, Y.; Su, Z.; Chen, Y. Carnosic Acid Ameliorated Aβ-mediated (Amyloid-β Peptide) Toxicity, Cholinergic Dysfunction and Mitochondrial Defect in C. elegans of Alzheimer's Model. FOOD FUNCT. 2022, 13. Art. No: 4640. DOI: 10.1039/D1FO02965G.

29. Yoshida, H.; Meng, P.; Matsumiya, T.; Tanji, K.; Hayakari, R.; Xing, F.; Wang, L.; Tsuruga, K.; Tanaka, H.; Mimura, J.; et al. Carnosic acid suppresses the production of amyloid-β 1-42 and 1-43 by inducing an α-secretase TACE/ADAM17 in U373MG human astrocytoma cells. Neurosci. Res. 2014, 79, 83-93. DOI: 10.1016/j.neures.2013.11.004

30. Liu, J.; Su, H.; Qu, Q. M. Carnosic Acid Prevents Beta-Amyloid-Induced Injury in Human Neuroblastoma SH-SY5Y Cells via the Induction of Autophagy. Neurochem. Res. 2016, 41 (9), 2311-2323. DOI: 10.1007/s11064-016-1945-6

31. Mirza, F. J.; Zahid, S.; Holsinger, R. M. D. Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action. Molecules 2023, 28 (5). Art. No: 2306. DOI: 10.3390/molecules28052306

32. Wu, C. R.; Tsai, C. W.; Chang, S. W.; Lin, C. Y.; Huang, L. C.; Tsai, C. W. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction. Chem. Biol. Interact. 2015, 225, 40-46. DOI: 10.1016/j.cbi.2014.11.011

33. Lipina, C.; Hundal, H. S. Carnosic acid stimulates glucose uptake in skeletal muscle cells via a PME-1/PP2A/PKB signalling axis. Cell. Signal. 2014, 26 (11), 2343-2349. DOI: 10.1016/j.cellsig.2014.07.022

34. Gaya, M.; Repetto, V.; Toneatto, J.; Anesini, C.; Piwien-Pilipuk, G.; Moreno, S. Antiadipogenic effect of carnosic acid, a natural compound present in Rosmarinus officinalis, is exerted through the C/EBPs and PPARγ pathways at the onset of the differentiation program. Biochim. Biophys. Acta. 2013, 1830 (6), 3796-3806. DOI: 10.1016/j.bbagen.2013.03.021

35. Ou, J.; Huang, J.; Zhao, D.; Du, B.; Wang, M. Protective effect of rosmarinic acid and carnosic acid against streptozotocin-induced oxidation, glycation, inflammation and microbiota imbalance in diabetic rats. FOOD FUNCT. 2018, 9 (2), 851-860. DOI: 10.1039/c7fo01508a

36. Quirarte-Báez, S. M.; Zamora-Perez, A. L.; Reyes-Estrada, C. A.; Gutiérrez-Hernández, R.; Sosa-Macías, M.; Galaviz-Hernández, C.; Manríquez, G. G. G.; Lazalde-Ramos, B. P. A shortened treatment with rosemary tea (Rosmarinus officinalis) instead of glucose in patients with diabetes mellitus type 2 (TSD). J. Popul. Ther. Clin. Pharmacol. 2019, 26 (4), 18-28. DOI: 10.15586/jptcp.v26i4.634

37. Wang, H.; Wang, J.; Liu, Y.; Ji, Y.; Guo, Y.; Zhao, J. Interaction mechanism of carnosic acid against glycosidase (α-amylase and α-glucosidase). Int. J. Biol. Macromol. 2019, 138, 846-853. DOI: 10.1016/j.ijbiomac.2019.07.179

38. Ojeda-Sana, A. M.; Repetto, V.; Moreno, S. Carnosic acid is an efflux pumps modulator by dissipation of the membrane potential in Enterococcus faecalis and Staphylococcus aureus. World J. Microbiol. Biotechnol. 2013, 29 (1), 137-144. DOI: 10.1007/s11274-012-1166-3

39. Souza, A. B.; de Souza, M. G.; Moreira, M. A.; Moreira, M. R.; Furtado, N. A.; Martins, C. H.; Bastos, J. K.; dos Santos, R. A.; Heleno, V. C.; Ambrosio, S. R.; Veneziani, R. C. Antimicrobial evaluation of diterpenes from Copaifera langsdorffii oleoresin against periodontal anaerobic bacteria. Molecules 2011, 16 (11), 9611-9619. DOI: 10.3390/molecules16119611

40. Islam, M. T. Diterpenes and Their Derivatives as Potential Anticancer Agents. Phytother. Res. 2017, 31 (5), 691-712. DOI: 10.1002/ptr.5800

41. Allegra, A.; Tonacci, A.; Pioggia, G.; Musolino, C.; Gangemi, S. Anticancer Activity of Rosmarinus officinalis L.: Mechanisms of Action and Therapeutic Potentials. Nutrients 2020, 12 (6). Art. No: 1739. DOI: 10.3390/nu12061739

42. Chan, E.; Wong, S.; Chan, H. An overview of the chemistry and anticancer properties of rosemary extract and its diterpenes. J. HerbMed Pharmacol. 2021, 11, 10-19. DOI: 10.34172/jhp.2022.02.

43. Kakouri, E.; Nikola, O.; Kanakis, C.; Hatziagapiou, K.; Lambrou, G. I.; Trigas, P.; Kanaka-Gantenbein, C.; Tarantilis, P. A. Cytotoxic Effect of Rosmarinus officinalis Extract on Glioblastoma and Rhabdomyosarcoma Cell Lines. Molecules 2022, 27 (19). Art. No: 6348. DOI: 10.3390/molecules27196348

44. Yesil-Celiktas, O.; Sevimli, C.; Bedir, E.; Vardar-Sukan, F. Inhibitory effects of rosemary extracts, carnosic acid and rosmarinic acid on the growth of various human cancer cell lines. Plant Foods Hum. Nutr. 2010, 65 (2), 158-163. DOI: 10.1007/s11130-010-0166-4

45. El-Huneidi, W.; Bajbouj, K.; Muhammad, J. S.; Vinod, A.; Shafarin, J.; Khoder, G.; Saleh, M. A.; Taneera, J.; Abu-Gharbieh, E. Carnosic Acid Induces Apoptosis and Inhibits Akt/mTOR Signaling in Human Gastric Cancer Cell Lines. Pharmaceuticals (Basel) 2021, 14 (3). Art. No: 230. DOI: 10.3390/ph14030230

46. Lin, L.; Wu, Q.; Lu, F.; Lei, J.; Zhou, Y.; Liu, Y.; Zhu, N.; Yu, Y.; Ning, Z.; She, T.; Hu, M. Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers. Front. Oncol. 2023, 13, Art. No: 1184079. DOI: 10.3389/fonc.2023.1184079

47. Telkoparan-Akillilar, P.; Panieri, E.; Cevik, D.; Suzen, S.; Saso, L. Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer. Molecules 2021, 26 (5). Art. No: 1417. DOI: 10.3390/molecules26051417

48. Yan, M.; Li, G.; Petiwala, S.; Householter, E. Standardized rosemary (Rosmarinus officinalis) extract induces Nrf2/sestrin-2 pathway in colon cancer cells. J. Funct. Food. 2015, 13, 137-147. DOI: 10.1016/j.jff.2014.12.038

49. Cykowiak, M.; Krajka-Kuźniak, V. Nrf2 jako terapeutyczny punkt uchwytu w profilaktyce i terapii chorób cywilizacyjnych. Farmacja Współczesna. 2019, 12, 42-49.

50. Magnelli, L.; Schiavone, N.; Staderini, F.; Biagioni, A.; Papucci, L. MAP Kinases Pathways in Gastric Cancer. Int. J. Mol. Sci. 2020, 21 (8), Art. No: 2893. DOI: 10.3390/ijms21082893 From NLM.

51. Boueroy, P.; Saensa‑Ard, S.; Siripong, P.; Kanthawong, S.; Hahnvajanawong, C. Rhinacanthin-C Extracted from Rhinacanthus nasutus (L.) Inhibits Cholangiocarcinoma Cell Migration and Invasion by Decreasing MMP-2, uPA, FAK and MAPK Pathways. Asian Pac. J. Cancer Prev. 2018, 19 (12), 3605-3613. DOI: 10.31557/apjcp.2018.19.12.3605

52. Jiang, S.; Qiu, Y.; Wang, Z.; Ji, Y.; Zhang, X.; Yan, X.; Zhan, Z. Carnosic Acid Induces Antiproliferation and Anti-Metastatic Property of Esophageal Cancer Cells via MAPK Signaling Pathways. J. Oncol. 2021, 2021, Art. No: 4451533. DOI: 10.1155/2021/4451533

53. Einbond, L. S.; Wu, H. A.; Kashiwazaki, R.; He, K.; Roller, M.; Su, T.; Wang, X.; Goldsberry, S. Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin. Fitoterapia 2012, 83 (7), 1160-1168. DOI: 10.1016/j.fitote.2012.07.006

54. Dang, C. T.; Shapiro, C. L.; Hudis, C. A. Potential role of selective COX-2 inhibitors in cancer management. Oncology (Williston Park) 2002, 16 (5 Suppl 4), 30-36.

55. Cao, Y.; Prescott, S. M. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J. Cell. Physiol. 2002, 190 (3), 279-286. DOI: 10.1002/jcp.10068

56. Tsujii, M.; Kawano, S.; DuBois, R. N. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl. Acad. Sci. U. S. A. 1997, 94 (7), 3336-3340. DOI: 10.1073/pnas.94.7.3336

57. Barni, M. V.; Carlini, M. J.; Cafferata, E. G.; Puricelli, L.; Moreno, S. Carnosic acid inhibits the proliferation and migration capacity of human colorectal cancer cells. Oncol. Rep. 2012, 27 (4), 1041-1048. DOI: 10.3892/or.2012.1630

58. Leeman, M. F.; Curran, S.; Murray, G. I. New insights into the roles of matrix metalloproteinases in colorectal cancer development and progression. J. Pathol. 2003, 201 (4), 528-534. DOI: 10.1002/path.1466

59. Cheung, K. J.; Ewald, A. J. A collective route to metastasis: Seeding by tumor cell clusters. Science 2016, 352 (6282), 167-169. DOI: 10.1126/science.aaf6546

60. Fares, J.; Fares, M.; Khachfe, H.; Salhab, H.; Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal. Transduct. Target. Ther. 2020, 5(1), Art. No: 28. DOI: 10.1038/s41392-020-0134-x

61. Kalluri, R.; Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 2009, 119 (6), 1420-1428. DOI: 10.1172/jci39104

62. Lamouille, S.; Xu, J.; Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell. Biol. 2014, 15 (3), 178-196. DOI: 10.1038/nrm3758

63. Park, S. Y.; Song, H.; Sung, M. K.; Kang, Y. H.; Lee, K. W.; Park, J. H. Carnosic acid inhibits the epithelial-mesenchymal transition in B16F10 melanoma cells: a possible mechanism for the inhibition of cell migration. Int. J. Mol. Sci. 2014, 15 (7), 12698-12713. DOI: 10.3390/ijms150712698

64. Wong, R. S. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011, 30 (1), Art. No: 87. DOI: 10.1186/1756-9966-30-87

65. Su, K.; Wang, C. F.; Zhang, Y.; Cai, Y. J.; Zhang, Y. Y.; Zhao, Q. The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway. Biomed. Pharmacother. 2016, 82, 180-191. DOI: 10.1016/j.biopha.2016.04.056

66. Gao, Q.; Liu, H.; Yao, Y.; Geng, L.; Zhang, X.; Jiang, L.; Shi, B.; Yang, F. Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. J. Appl. Toxicol. 2015, 35 (5), 485-492. DOI: 10.1002/jat.3049

67. Dereń-Wagemann, I.; Kiełbiński, M.; Kuliczkowski, K. Autofagia – proces o dwóch obliczach. Acta Haematol. Pol. 2013, 44 (4), 383-391. DOI: 10.1016/j.achaem.2013.05.003

68. O'Neill, E. J.; Sze, N. S. K.; MacPherson, R. E. K.; Tsiani, E. Carnosic Acid against Lung Cancer: Induction of Autophagy and Activation of Sestrin-2/LKB1/AMPK Signalling. Int. J. Mol. Sci. 2024, 25 (4). Art. No: 1950. DOI: 10.3390/ijms25041950

69. Nabekura, T.; Yamaki, T.; Hiroi, T.; Ueno, K.; Kitagawa, S. Inhibition of anticancer drug efflux transporter P-glycoprotein by rosemary phytochemicals. Pharmacol. Res. 2010, 61 (3), 259-263. DOI: 10.1016/j.phrs.2009.11.010

70. ÖZenver, N.; Efferth, T. Cancer combination therapy with carnosic acid. Biocell 2022, 46 (10), 2151-2157. DOI: 10.32604/biocell.2022.019937

71. Shao, N.; Mao, J.; Xue, L.; Wang, R.; Zhi, F.; Lan, Q. Carnosic acid potentiates the anticancer effect of temozolomide by inducing apoptosis and autophagy in glioma. J. Neurooncol. 2019, 141 (2), 277-288. DOI: 10.1007/s11060-018-03043-5

72. González-Vallinas, M.; Molina, S.; Vicente, G.; de la Cueva, A.; Vargas, T.; Santoyo, S.; García-Risco, M. R.; Fornari, T.; Reglero, G.; Ramírez de Molina, A. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells. Pharmacol. Res. 2013, 72, 61-68. DOI: 10.1016/j.phrs.2013.03.010

73. Gocek, E.; Studzinski, G. P. Vitamin D and differentiation in cancer. Crit. Rev. Clin. Lab. Sci. 2009, 46 (4), 190-209. DOI: 10.1080/10408360902982128

74. Sharabani, H.; Izumchenko, E.; Wang, Q.; Kreinin, R.; Steiner, M.; Barvish, Z.; Kafka, M.; Sharoni, Y.; Levy, J.; Uskokovic, M.; et al. Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. Int. J. Cancer 2006, 118 (12), 3012-3021. DOI: 10.1002/ijc.21736

75. Fotio, Y.; Aboufares El Alaoui, A.; Borruto, A. M.; Acciarini, S.; Giordano, A.; Ciccocioppo, R. Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain: A Preclinical Study. Front. Pharmacol. 2019, 10, Art. No: 711. DOI: 10.3389/fphar.2019.00711

76. Gianni, W.; Carlo, M.; Colangelo, L.; Grotta, G.; Sonato, C.; Cilli, M.; Toto, A.; Minisola, S. Short-term efficacy of a fixed association of Palmitoylethanolamide and other phytochemicals as add-on therapy in the management of chronic pain in elderly patients: a real-world retrospective study. Geriatric Care 2018, 4. Art. No: 7177. DOI: 10.4081/gc.2018.7177

77. Newman, D. J.; Cragg, G. M. Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010. J. Nat. Prod. 2012, 75 (3), 311-335. DOI: 10.1021/np200906s

78. Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79(3), 629-661. DOI: 10.1021/acs.jnatprod.‌5b01055

Magdalena Wojtczuk

Affiliation:

Student Scientific Association, Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland Poland

Agnieszka Dominiak

agnieszka.dominiak@wum.edu.pl

Affiliation:

WUM