Indirubin

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Indirubin

Common Names

  • Indigo

For Patients & Caregivers

How It Works

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 laboratory. 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.

Purported Uses
  • 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.
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.
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.
  • 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.
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). 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). In patients with Crohn’s disease, preliminary analyses suggest only modest benefit (28).

Interim trial analysis of an oral chemotherapy with 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
  • Cancer treatment
  • 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)

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. In one case, alleviation of the condition required surgery (32). In addition, these researchers note other reports of ischemic lesions of the colonic mucosa.
  • 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.
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. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Zhang JT. New drugs derived from medicinal plants. Therapie. 2002;57:137-50.

  9. Shin EK, Kim JK. Indirubin derivative E804 inhibits angiogenesis. BMC Cancer. 2012 May 3;12:164.

  10. Cheng X, Merz KH. The Role of Indirubins in Inflammation and Associated Tumorigenesis. Adv Exp Med Biol. 2016;929:269-290.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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. Aug 7 2019.

  16. 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.

  17. Matsuno Y, Hirano A, Esaki M. Possible Association of Phlebitis-Induced Colitis With Indigo naturalis. Gastroenterology. Aug 2018;155(2):576-577.

  18. 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.

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