Indirubin

• How It Works

  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 this 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.
• 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.
• Scientific Name

  Indigofera tinctoria

• Clinical Summary

  Indirubin is extracted from the indigo plant (Isatis Root, Isatis Leaf). It is a constituent of the 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 phases by selectively inhibiting cyclin-dependent kinases (CDK) ⁽⁴⁾ by interacting 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, cyclin D1 inhibition, and caspase-3 activation ⁽¹⁾. Indirubin may also play a role in inhibiting microtubule assembly, further reducing the rate of cell reproduction ⁽¹¹⁾. Its anti-inflammatory effects may be due to interferon-gamma inhibition ⁽²⁾.

  Indirubin is a minor constituent of Indigofera tinctoria; 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 antiproliferative activity against human HT-29 colorectal cancer cells in a solid tumor model ⁽⁹⁾. IDR-E804, another indirubin derivative, 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-2, AKT, and extracellular signal regulated kinases ⁽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⁾.

  Indirubin modulates proliferation and differentiation of keratinocytes derived from patients with psoriasis  ⁽¹⁰⁾.

• 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⁾.

• References

  1. 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.