Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4, and MKK7 in human melanoma

Nu Ry Song, Eunjung Lee, Sanguine Byun, Jong Eun Kim, Madhusoodanan Mottamal, Jung Han Yoon Park, Soon Sung Lim, Ann M. Bode, Hyong Joo Lee, Ki Won Lee, Zigang Dong

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Abstract

Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.

Original languageEnglish
Pages (from-to)1293-1303
Number of pages11
JournalCancer Prevention Research
Volume6
Issue number12
DOIs
Publication statusPublished - 2013 Dec 1

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Song, N. R., Lee, E., Byun, S., Kim, J. E., Mottamal, M., Park, J. H. Y., Lim, S. S., Bode, A. M., Lee, H. J., Lee, K. W., & Dong, Z. (2013). Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4, and MKK7 in human melanoma. Cancer Prevention Research, 6(12), 1293-1303. https://doi.org/10.1158/1940-6207.CAPR-13-0134