Review of Shikonin and Derivatives: Isolation, Chemistry, Biosynthesis, Pharmacology and Toxicology

Overview

Journal Front Pharmacol

Date 2022 Jul 18

PMID 35847041

Authors

Snehlata Yadav

Ajay Sharma

Gulzar Ahmad Nayik

Raymond Cooper

Garima Bhardwaj

Harvinder Singh Sohal

Vishal Mutreja

Ramandeep Kaur

Franklin Ore Areche

Mohannad AlOudat

Ayaz Mukarram Shaikh

Bela Kovacs

Abdelhakam Esmaeil Mohamed Ahmed

Affiliations

Soon will be listed here.

Abstract

Shikonin and its derivatives, isolated from traditional medicinal plant species of the genus belonging to the Boraginaceae family, have numerous applications in foods, cosmetics, and textiles. Shikonin, a potent bioactive red pigment, has been used in traditional medicinal systems to cure various ailments and is well known for its diverse pharmacological potential such as anticancer, antithrombotic, neuroprotective, antidiabetic, antiviral, anti-inflammatory, anti-gonadotropic, antioxidants, antimicrobial and insecticidal. Herein, updated research on the natural sources, pharmacology, toxicity studies, and various patents filed worldwide related to shikonin and approaches to shikonin's biogenic and chemical synthesis are reviewed. Furthermore, recent studies to establish reliable production systems to meet market demand, functional identification, and future clinical development of shikonin and its derivatives against various diseases are presented.

Citing Articles

Shikonin protects mitochondria through the NFAT5/AMPK pathway for the treatment of diabetic wounds.

Cen L, Cao Y, Zhou Y, Guo J, Xue J World J Diabetes. 2024; 15(12):2338-2352.

PMID: 39676806 PMC: 11580590. DOI: 10.4239/wjd.v15.i12.2338.

Natural pigments derived from plants and microorganisms: classification, biosynthesis, and applications.

Tang Q, Li Z, Chen N, Luo X, Zhao Q Plant Biotechnol J. 2024; 23(2):592-614.

PMID: 39642082 PMC: 11772333. DOI: 10.1111/pbi.14522.

Metabolites Obtained from Boraginaceae Plants as Potential Cosmetic Ingredients-A Review.

Chrzanowska E, Denisow B, Ekiert H, Pietrzyk L Molecules. 2024; 29(21).

PMID: 39519729 PMC: 11547297. DOI: 10.3390/molecules29215088.

Bioactive stem cell-laden 3D nanofibrous scaffolds for tissue engineering.

Natouri O, Barzegar A, Nobakht A, Bagheri A, Eslami F, Jafarirad S Heliyon. 2024; 10(19):e38462.

PMID: 39403461 PMC: 11471473. DOI: 10.1016/j.heliyon.2024.e38462.

High-Altitude Medicinal Plants as Promising Source of Phytochemical Antioxidants to Combat Lifestyle-Associated Oxidative Stress-Induced Disorders.

Ashraf M, Khan S, Misri S, Gaira K, Rawat S, Rawat B Pharmaceuticals (Basel). 2024; 17(8).

PMID: 39204080 PMC: 11357401. DOI: 10.3390/ph17080975.

References

Fayez H, El-Motaleb M, Selim A . Synergistic Cytotoxicity Of Shikonin-Silver Nanoparticles As An Opportunity For Lung Cancer. J Labelled Comp Radiopharm. 2019; 63(1):25-32. DOI: 10.1002/jlcr.3818. View

Yeh Y, Liu T, Lai H . Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression. Evid Based Complement Alternat Med. 2015; 2015:620383. PMC: 4337265. DOI: 10.1155/2015/620383. View

Nam C, Hwang J, Kim M, Choi Y, Han K, Kang J . Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs. Toxicol Res. 2015; 31(1):77-88. PMC: 4395658. DOI: 10.5487/TR.2015.31.1.077. View

Malik S, Bhushan S, Sharma M, Ahuja P . Physico-chemical factors influencing the shikonin derivatives production in cell suspension cultures of Arnebia euchroma (Royle) Johnston, a medicinally important plant species. Cell Biol Int. 2010; 35(2):153-8. DOI: 10.1042/CBI20090459. View

Yamashita K, Miyazaki H, Shinoda S, Hagiwara S, Takahashi H, Itagaki H . Assessment of the skin sensitizing potential of chemicals, contained in foods and/or cosmetic ingredients, using a modified local lymph node assay with an elicitation phase (LLNA:DAE) method. J Toxicol Sci. 2018; 43(8):513-520. DOI: 10.2131/jts.43.513. View

Huang X, Fu H, Tang H, Yin Z, Zhang W, Shu G . Optimization Extraction of Shikonin Using Ultrasound-Assisted Response Surface Methodology and Antibacterial Studies. Evid Based Complement Alternat Med. 2020; 2020:1208617. PMC: 7411493. DOI: 10.1155/2020/1208617. View

Cao H, Liu D, Lai Y, Chen Y, Yu L, Shao M . Inhibition of the STAT3 Signaling Pathway Contributes to the Anti-Melanoma Activities of Shikonin. Front Pharmacol. 2020; 11:748. PMC: 7267064. DOI: 10.3389/fphar.2020.00748. View

Kumar A, Shashni S, Kumar P, Pant D, Singh A, Verma R . Phytochemical constituents, distributions and traditional usages of Arnebia euchroma: A review. J Ethnopharmacol. 2021; 271:113896. DOI: 10.1016/j.jep.2021.113896. View

Newman J, Chappell J . Isoprenoid biosynthesis in plants: carbon partitioning within the cytoplasmic pathway. Crit Rev Biochem Mol Biol. 1999; 34(2):95-106. DOI: 10.1080/10409239991209228. View

10.

Fan C, Lim L, Loh S, Lim K, Upton Z, Leavesley D . Application of "macromolecular crowding" in vitro to investigate the naphthoquinones shikonin, naphthazarin and related analogues for the treatment of dermal scars. Chem Biol Interact. 2019; 310:108747. DOI: 10.1016/j.cbi.2019.108747. View

11.

Lange B, Severin K, Bechthold A, Heide L . Regulatory role of microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase for shikonin biosynthesis in Lithospermum erythrorhizon cell suspension cultures. Planta. 1998; 204(2):234-41. DOI: 10.1007/s004250050252. View

12.

Rajasekar S, Park D, Park C, Park S, Park Y, Kim S . In vitro and in vivo anticancer effects of Lithospermum erythrorhizon extract on B16F10 murine melanoma. J Ethnopharmacol. 2012; 144(2):335-45. DOI: 10.1016/j.jep.2012.09.017. View

13.

Li J, Zhao M, Sun M, Wu S, Zhang H, Dai Y . Multifunctional Nanoparticles Boost Cancer Immunotherapy Based on Modulating the Immunosuppressive Tumor Microenvironment. ACS Appl Mater Interfaces. 2020; 12(45):50734-50747. DOI: 10.1021/acsami.0c14909. View

14.

Andujar I, Recio M, Bacelli T, Giner R, Rios J . Shikonin reduces oedema induced by phorbol ester by interfering with IkappaBalpha degradation thus inhibiting translocation of NF-kappaB to the nucleus. Br J Pharmacol. 2010; 160(2):376-88. PMC: 2874859. DOI: 10.1111/j.1476-5381.2010.00696.x. View

15.

Lin H, Han H, Sun W, Yang Y, Tang C, Lu G . Design and characterization of α-lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors. Eur J Med Chem. 2017; 144:137-150. DOI: 10.1016/j.ejmech.2017.12.019. View

16.

Oshikiri H, Watanabe B, Yamamoto H, Yazaki K, Takanashi K . Two BAHD Acyltransferases Catalyze the Last Step in the Shikonin/Alkannin Biosynthetic Pathway. Plant Physiol. 2020; 184(2):753-761. PMC: 7536692. DOI: 10.1104/pp.20.00207. View

17.

Yazaki K, Fukui H, Kikuma M, Tabata M . Regulation of shikonin production by glutamine in Lithospermum erythrorhizon cell cultures. Plant Cell Rep. 2013; 6(2):131-4. DOI: 10.1007/BF00276670. View

18.

Sun Q, Gong T, Liu M, Ren S, Yang H, Zeng S . Shikonin, a naphthalene ingredient: Therapeutic actions, pharmacokinetics, toxicology, clinical trials and pharmaceutical researches. Phytomedicine. 2021; 94:153805. DOI: 10.1016/j.phymed.2021.153805. View

19.

Kohle A, Sommer S, Yazaki K, Ferrer A, Boronat A, Li S . High level expression of chorismate pyruvate-lyase (UbiC) and HMG-CoA reductase in hairy root cultures of Lithospermum erythrorhizon. Plant Cell Physiol. 2002; 43(8):894-902. DOI: 10.1093/pcp/pcf106. View

20.

Shen X, Wang Y, Han X, Sheng L, Wu F, Liu X . Design, synthesis and anticancer activity of naphthoquinone derivatives. J Enzyme Inhib Med Chem. 2020; 35(1):773-785. PMC: 7144209. DOI: 10.1080/14756366.2020.1740693. View