Health Care Professional Information

Scientific Name
Indigofera tinctoria
Common Name

Indigo

Clinical Summary

Indirubin is extracted from the Indigo plant (Isatis Root, Isatis Leaf). It is a constituent of a traditional Chinese herbal formula, Dang Gui Long Hui Wan used in the treatment of chronic myelogenous leukemia (CML). Indirubin has also been used in Asia as a systemic treatment for psoriasis.

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 derivate of indirubin was shown to enhance the cytotoxic effects of adriamycin (17).
Clinical studies show efficacy of indirubin in the treatment of psoriasis (18).

A small study of indirubin in patients with head and neck cancer found a reduction in mucosal damage from radiation therapy (3). Meisoindigo, a metabolite of indirubin has also been shown to have similar properties (4). A few cases of positive effects following long term use of indirubin for the treatment of CML (7) have been reported. However further clinical trials are needed to confirm its role.

Purported Uses
  • Cancer treatment
  • Inflammation
  • Psoriasis
Mechanism of Action

Indirubin inhibits DNA synthesis in rats and cell proliferation in the late-G1 and G2/M phase by selectively inhibiting cyclin-dependent kinases (CDK) (4) through the interaction with the kinase's ATP-binding site (6). Indirubin-3-oxime inhibits the growth of human laryngeal cancer cells via induction of CDK inhibitor p21, inhibition of cyclin D1 and activation of caspase-3 (1). Indirubin may also play a role in inhibiting the assembly of microtubules, further reducing the rate of cell reproduction (11). Its anti-inflammatory effects appear to be due to inhibition of interferon-gamma (2). Indirubin is a minor constituent of Indigofera tinctoria, however a synthetic form of the substance was shown to have similar effectiveness against CML (12) (13). One study investigated the inhibitory effect of six indirubin derivatives against HL-60 human promyelocytic leukemia cells (8). One of these derivatives strongly inhibited the growth of HL-60 cancer cells, whereas the others showed only weak cytotoxic activity. An additional study found that four indirubin derivatives exhibited an antiproliferative activity against human HT-29 colorectal cancer cells in a solid tumor model (9). Indirubin modulates the proliferation and differentiation of keratinocytes derived from patients with psoriasis (10).
A derivative of indirubin, IDR-E804 was shown to inhibit angiogenesis by decreasing proliferation, migration and tube formation of vascular endothelial growth factor VEGF-treated human umbilical vein endothelial cells. These effects were accompanied by decreased phosphorylation of VEGF receptor (VEGFR)-2, AKT and extracellular signal regulated kinase (19).
Another study reported that mitochondrial dysfunction may be an important mechanism via which indirubin-3'-oxime induces cell cycle arrest in human neuroblastoma cells (20).

Adverse Reactions

Reported (Oral): Mild to severe nausea, vomiting, abdominal pain, diarrhea, headache and edema. A few patients were found to have pulmonary arterial hypertension and cardiac insufficiency following long-term treatment (4). Long term oral ingestion has also occasionally been associated with hepatitis (10).

Literature Summary and Critique

You WC, et al. Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis. J Altern Complement Med. 2009 Jul;15(7):771-8.
This study investigated the effect of indirubin (taken as indigowood root powder) on acute radiation induced mucositis. Twenty patients who were receiving radiation therapy for head and neck cancer were enrolled and randomized into a control or treatment group. The treatment group gargled with a solution made from indigowood root powder dissolved in double-distilled water for three minutes, and then swallowed it, before meals daily for seven weeks. The results of the clinical trial indicated that indigo wood root significantly reduced the severity of radiation mucositis (p=0.01), anorexia (p=0.002), and swallowing difficulty (p=0.002) in treated patients compared to the control group. The authors concluded that indirubin may play a therapeutic role in improving radiation mucositis, anorexia, and difficulty swallowing, but that the exact mechanism and pathways should be further studied.

Dosage (Inside MSKCC Only)
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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.

Consumer Information

How It Works

Bottom Line: Indirubin has not been shown to prevent or treat cancer in humans.

Indirubin is derived from the Indigo Plant (Isatis Root, Isatis Leaf). It is used as part of a traditional Chinese herbal prescription called Dang Gui Long Hui Wan, to treat chronic myelogenous leukemia (CML). Studies have shown that the substance can help keep cancer cells from reproducing in rats. Indirubin also appears to reduce inflammation by inhibiting part of the immune response. In addition to being extracted from the plant, Indirubin may also be created synthetically in the laboratory.

Purported Uses
  • To treat chronic myelogenous leukemia
    Laboratory and animal studies support this use. Clinical trials have not yet been conducted.
  • To reduce inflammation
    The results of a small study in patients with head and neck cancer suggest that the anti-inflammatory properties of indirubin (taken as indigowood root powder) reduce mucosal damage from radiation therapy. However further clinical studies are needed to confirm this effect.
  • To treat Psoriasis
    A few studies show that Indirubin is effective against psoriasis.
Research Evidence

Reduce mucosal inflammation from radiation therapy:
A small clinical study enrolled 20 patients with head and neck cancer. Ten of these patients received indirubin (taken as indigowood root powder) for seven weeks during radiation therapy. The results of the study indicated that patients receiving this treatment had significantly less radiation mucositis, anorexia, and difficulty swallowing compared to the untreated patients.

Side Effects
  • Mild to severe nausea
  • Vomiting
  • Abdominal pain
  • Diarrhea
  • Headache
  • Edema
  • In patients treated over a long time, blood flow to the heart and lungs may be affected.
Special Point
  • Meisoindigo, which is derived from indirubin, has been shown to have similar properties.
  • This product is currently not sold as a dietary supplement. It is only available for preclinical and clinical studies.
E-mail your questions and comments to aboutherbs@mskcc.org.