Indirubin

Purported Benefits, Side Effects & More
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Indirubin

Purported Benefits, Side Effects & More
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Indirubin

Common Names

  • Indigo

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For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.

What is it?

Evidence on whether indirubin can treat chronic conditions is lacking.

Indirubin is derived from the Indigo Plant (Isatis Root, Isatis Leaf). It has also been created synthetically in the lab. In Asia, it is part of combination formulas used clinically and in traditional herbal prescriptions to treat chronic conditions such as inflammation, gastrointestinal diseases, and some forms of cancer. Animal studies suggest this substance may help keep cancer cells from reproducing. Indirubin may also reduce inflammation by inhibiting part of the immune response.

Studies of indirubin in humans are very limited and side effects with some formulations have been reported. Well-designed clinical trials are needed to confirm safety and effectiveness of this compound for various conditions.

What are the potential uses and benefits?
  • To treat cancer

    There is a lack of evidence to support this use. Case reports and initial analyses suggest possible benefits in leukemia, but well-designed clinical trials are needed to confirm safety and effectiveness.
  • To reduce inflammation

    A small study in patients with head and neck cancer suggest that indirubin, taken as indigowood root powder, may reduce mucosal damage from radiation therapy. Additional studies are needed to confirm this effect.
  • To treat psoriasis

    A few studies suggest topical formulations can treat inflammatory skin conditions such as psoriasis and contact dermatitis.
  • To treat gastrointestinal conditions

    Oral I. naturalis has been used in clinical trials in Asia for ulcerative colitis and other gastrointestinal conditions, but results are preliminary and severe adverse events have been reported.
What are the side effects?

With oral I. naturalis: Liver dysfunction, abdominal pain, nausea, and headache

Case reports

  • Inflamed colon: In 2 women with a history ulcerative colitis who took oral I. naturalis. In one case, alleviation of the condition required surgery.
  • Lower abdominal pain and bloody stools: Caused by self-treatment with I. naturalis in a 44-year-old woman with ulcerative colitis who used this product for several months to replace her standard medications.
  • Bluish-black patches in the small intestine: Related to the use of I. naturalis in a 57-year-old woman with Crohn's disease.
  • Inflamed pancreas: In an 11-year old boy after 2 doses of I. naturalis to treat Crohn's disease. The condition improved after the product was discontinued.
  • High blood pressure that affects the lung and heart: A serious condition known as pulmonary arterial hypertension has been reported in multiple cases of patients treated with oral I. naturalis for ulcerative colitis. Symptoms have included swelling, shortness of breath, cold limbs, and chest pain and required acute medical care.
What else do I need to know?

Patient Warnings:

  • There have been serious adverse effects in patients treated with oral I. naturalis for gastrointestinal conditions. Therefore, this product should not be used outside of clinical trials.

Do Not Take if:

You are taking CYP450 3A4 substrate drugs: Lab studies suggest that indirubin, a component of the isatis plant, may affect how these drugs are metabolized. Clinical relevance has yet to be determined.

Special Point:

  • This product is currently not sold as a dietary supplement. It is only available for preclinical and clinical studies.
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For Healthcare Professionals

Scientific Name
Indigofera tinctoria, Indigo naturalis
Clinical Summary

Indirubin is extracted from the indigo plant (Isatis Root, Isatis Leaf). It is a part of combination formulas used in traditional Chinese medicine (TCM) and clinically in Asia to treat chronic conditions including inflammation, gastrointestinal diseases, and some forms of cancer (21). For example, Dang Gui Long Hui Wan which contains Indigofera tinctoria has been used to treat chronic myelogenous leukemia (CML), while Qing Dai (Indigo naturalis) has been used topically for psoriasis and orally for ulcerative colitis.

In vitro and animal studies indicate anti-inflammatory (2), antitumor (14) (15), antiangiogenic (19), and neuroprotective (16) effects. Indirubin also inhibits cyclin-dependent kinases in tumor cells (5) (6). A derivative of indirubin enhanced the cytotoxic effects of adriamycin (17).

Studies of indirubin in humans are limited. A few clinical trials suggest topical I. naturalis ointment is effective for psoriasis (18) (22) and atopic dermatitis (23) (35). Oral I. naturalis induced a clinical response in ulcerative colitis (24) (25), but the trial was stopped due to a prior case of pulmonary arterial hypertension, possibly related to a self-purchased product (26). In addition, a subsequent national survey in Japan identified 11 cases of PAH in UC patients as well as other adverse events (27). Short-term indigo administration in patients with mild to moderate UC appeared to be effective without serious adverse events, but the study was small and additional research is needed (36). In patients with Crohn’s disease, preliminary analyses suggest only modest benefit (28).

Interim trial analysis of oral chemotherapy with an I. naturalis formulation versus intravenous chemotherapy for acute promyelocytic leukemia suggests it is as effective and may reduce hospital stays (29), but the final analysis has yet to be published. A small study of indirubin in the form of indigowood root powder for patients with head and neck cancer found a reduction in mucosal damage from radiation therapy (3). Although there are case reports of positive effects following long-term use of indirubin in CML (7), well-designed clinical trials are needed to confirm its role.

Purported Uses and Benefits
  • Cancer
  • Inflammation
  • Psoriasis
  • GI conditions
Mechanism of Action

Aryl hydrocarbon receptor (AhR) ligand, the active component of Indigo naturalis, may promote mucosal healing via induction of IL-22 from innate lymphoid cells (30). Indirubin and derivatives modulate inflammation-associated signaling including NF-kappaB, STAT3, TGF-ss, and AhR (21). In human skin samples, indirubin produced anti-psoriatic effects by modulating proliferation and differentiation of keratinocytes (10).

Anticancer and neuroprotective properties are attributed to inhibition of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 by competing with ATP binding sites (31). Indirubin-3-oxime inhibits growth of human laryngeal cancer cells via CDK inhibitor p21, cyclin D1 inhibition, and caspase-3 activation (1). In human neuroblastoma cells, it may induce cell-cycle arrest by altering mitochondrial function (20). Indirubin may also help inhibit microtubule assembly to further reduce rates of cell reproduction (11). In vivo, antiangiogenic and antiproliferative effects of an indirubin derivative was attributed in part to inhibition of VEGF/VEGFR-2 signaling (19).

Warnings

With oral I. naturalis, there have been reports of phlebitis-induced colitis, ischemic lesions of the colonic mucosa, or pulmonary arterial hypertension (24) (26) (27) (28) (32). Therefore, this product should not be used outside of clinical trials.

Adverse Reactions

Oral I. naturalis: Liver dysfunction, abdominal pain, nausea, and headache (24) (27) (32) (36)

Case reports

  • Pulmonary arterial hypertension: Multiple cases in patients with ulcerative colitis treated with I. naturalis (24) (26) (27).
  • Phlebitis-induced colitis: In 2 women with a history ulcerative colitis who took oral I. naturalis; one case required surgery (32). Researchers also noted other reports of ischemic lesions of the colonic mucosa.
  • Ischemic colitis: Induced by self-treatment with I. naturalis in a 44-year-old woman with ulcerative colitis who used this product for several months to replace her standard medications (37).
  • Acute pancreatitis: In an 11-year old boy after 2 doses of I. naturalis to treat pediatric Crohn’s disease (33). The condition improved after the product was discontinued.
  • Pseudomelanosis: Identified during endoscopy and related to the use of I. naturalis in a 57-year-old woman with Crohn’s disease (38).
Herb-Drug Interactions

CYP450 3A4 substrate drugs: Indirubin, a component of the isatis plant, activates CYP3A4 gene transcription through the human pregnane receptor. Clinical relevance is not yet known (34).

Dosage (OneMSK Only)
References
  1. Kameswaran TR, Ramanibai R. Indirubin-3-monooxime induced cell cycle arrest and apoptosis in Hep-2 human laryngeal carcinoma cells. Biomed Pharmacother. 2009;63(2):146-54.
  2. Kunikata T, Tatefuji T, Aga H, Iwaki K, Ikeda M, Kurimoto M. Indirubin inhibits inflammatory reactions in delayed-type hypersensitivity. Eur J Pharmacol. 2000;410:93-100.
  3. You WC, Hsieh CC, Huang JT. Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis.. J Altern Complement Med. 2009;15(7):771-8.
  4. Xiao Z, Hao Y, Liu B, Qian L. Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Leuk Lymphoma 2002;43:1763-8.
  5. Marko D, Schatzle S, Friedel A, Genzlinger A, Zankl H, Meijer L et al. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 2001;84:283-9.
  6. Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P et al. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol. 1999;1:60-7.
  7. Chen F, Li L, Ma D, et al. Imatinib achieved complete cytogenetic response in a CML patient received 32-year indirubin and its derivative treatment. Leuk Res. 2010 Feb;34(2):e75-7.
  8. Cuong NM, Tai BH, Hoan DH, et al. Inhibitory effects of indirubin derivatives on the growth of HL-60 leukemia cells. Nat Prod Commun. 2010 Jan;5(1):103-6.
  9. Kim SH, Choi SJ, Kim YC, Kuh HJ. Anti-tumor activity of noble indirubin derivatives in human solid tumor models in vitro. Arch Pharm Res. 2009 Jun;32(6):915-22.
  10. Lin YK, Leu YL, Yang SH, et al. Anti-psoriatic effects of Indigo naturalis on the proliferation and differentiation of keratinocytes with indirubin as the active component. J Dermatol Sci. 2009 Jun;54(3):168-74.
  11. Steriti R. Nutritional support for chronic myelogenous and other leukemias: a review of the scientific literature. Altern Med Rev. 2002;7:404-9.
  12. Han R. Highlight on the studies of anticancer drugs derived from plants in China. Stem Cells. 1994;12:53-63.
  13. Zhang JT. New drugs derived from medicinal plants. Therapie. 2002;57:137-50.
  14. Kim SA, Kwon SM, Kim JA, et al. 5’-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin ß1/FAK/Akt signaling. Cancer Lett. 2011 Jul 28;306(2):197-204.
  15. Williams SP, Nowicki MO, Liu F, et al. Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res. 2011 Aug 15;71(16):5374-80.
  16. Martin L, Magnaudeix A, Wilson CM, Yardin C, Terro F. The new indirubin derivative inhibitors of glycogen synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured neurons. J Neurosci Res. 2011 Nov;89(11):1802-11.
  17. Shi R, Li W, Zhang X, et al. A novel indirubin derivative PHII-7 potentiates Adriamycin cytotoxicity via inhibiting P-glycoprotein expression in human breast cancer MCF-7/ADR cells. Eur J Pharmacol. 2011 Nov 1;669(1-3):38-44.
  18. Lin YK, See LC, Huang YH, et al. Comparison of refined and crude Indigo naturalis ointment in treating psoriasis: randomized, observer-blind, controlled, intrapatient trial. Arch Dermatol. 2012 Mar;148(3):397-400.
  19. Shin EK, Kim JK. Indirubin derivative E804 inhibits angiogenesis. BMC Cancer. 2012 May 3;12:164.
  20. Liao XM, Leung KN. Indirubin-3’-oxime induces mitochondrial dysfunction and triggers growth inhibition and cell cycle arrest in human neuroblastoma cells. Oncol Rep. 2013 Jan;29(1):371-9.
  21. Cheng X, Merz KH. The Role of Indirubins in Inflammation and Associated Tumorigenesis. Adv Exp Med Biol. 2016;929:269-290.
  22. Lin YK, See LC, Huang YH, et al. Comparison of indirubin concentrations in Indigo naturalis ointment for psoriasis treatment: a randomized, double-blind, dosage-controlled trial. Br J Dermatol. Jan 2018;178(1):124-131.
  23. Lin YK, Chang SH, Yang CY, et al. Efficacy and safety of Indigo naturalis ointment in Treating Atopic Dermatitis: A randomized clinical trial. J Ethnopharmacol. Dec 12 2019:112477.
  24. Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of Indigo naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis. Gastroenterology. Mar 2018;154(4):935-947.
  25. Naganuma M, Sugimoto S, Fukuda T, et al. Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study. J Gastroenterol. 2020 Feb;55(2):169-180.
  26. Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J. Jul 1 2016;37(25):1992.
  27. Naganuma M, Sugimoto S, Suzuki H, et al. Adverse events in patients with ulcerative colitis treated with Indigo naturalis: a Japanese nationwide survey. J Gastroenterol. Oct 2019;54(10):891-896.
  28. Matsuno Y, Hirano A, Torisu T, et al. Short-term and long-term outcomes of Indigo naturalis treatment for inflammatory bowel disease. J Gastroenterol Hepatol. 2020 Mar;35(3):412-417.
  29. Yang MH, Wan WQ, Luo JS, et al. Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study. Am J Hematol. Dec 2018;93(12):1467-1473.
  30. Naganuma M. Treatment with Indigo naturalis for inflammatory bowel disease and other immune diseases. Immunol Med. Mar 2019;42(1):16-21.
  31. Wang Y, Hoi PM, Chan JY, et al. New perspective on the dual functions of indirubins in cancer therapy and neuroprotection. Anticancer Agents Med Chem. 2014;14(9):1213-1219.
  32. Matsuno Y, Hirano A, Esaki M. Possible Association of Phlebitis-Induced Colitis With Indigo naturalis. Gastroenterology. Aug 2018;155(2):576-577.
  33. Kim HA, Suh HR, Kang B, et al. Acute pancreatitis associated with Indigo naturalis in pediatric severe Crohn’s disease. Intest Res. Jan 2019;17(1):144-148.
  34. Kumagai T, Aratsu Y, Sugawara R, et al. Indirubin, a component of Ban-Lan-Gen, activates CYP3A4 gene transcription through the human pregnane X receptor. Drug Metab Pharmacokinet. Apr 2016;31(2):139-145.
  35. Lin YK, Chang SH, Yang CY, et al. Efficacy and safety of Indigo naturalis ointment in Treating Atopic Dermatitis: A randomized clinical trial. J Ethnopharmacol. Mar 25 2020;250:112477.
  36. Uchiyama K, Takami S, Suzuki H, et al. Efficacy and safety of short-term therapy with Indigo naturalis for ulcerative colitis: An investigator-initiated multicenter double-blind clinical trial. PLoS One. 2020;15(11):e0241337.
  37. Cho B, Yoon SM, Son SM, et al. Ischemic colitis induced by Indigo naturalis in a patient with ulcerative colitis: a case report. BMC Gastroenterol. May 15 2020;20(1):154.
  38. Le PH, Kuo CJ, Wu RC. Colonic Bluish-Black Patches in a 57-Year-Old Woman with Crohn’s Disease. Gastroenterology. Sep 2021;161(3):e10-e11.
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