Indole-3-carbinol enhances ultraviolet B-induced apoptosis by sensitizing human melanoma cells

Kim, Dong-Seok; Jeong, Yun-Mi; Moon, Sun Hee; Kim, Soyoung; Kwon, Sun Il; Park, Eun-Sang; Youn, Sung Won; Park, Kyoung-Chan

doi:10.1007/s00018-006-6306-1

Cited by 42 publications

(32 citation statements)

References 26 publications

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“…It was also reported that I3C exerted its activity only when administered orally and not by intraperitoneal injection (32,33). Other researchers also reported that DIM has stronger effects than I3C to prevent proliferation or to induce apoptosis in various tumor cells (28,29,(34)(35)(36). In this study, we showed that DIM possessed stronger antiangiogenic activities than I3C, further confirming that I3C may exert its biological activities in vivo by being converted into more effective DIM with a longer half-life in blood.…”

Section: Discussionsupporting

confidence: 90%

“…I3C exhibits biological activities such as antiproliferative and proapoptotic against tumor or endothelial cells, but the effective concentrations of I3C used in those experiments were relatively high (.100 mmol/L in most cases) (14,(27)(28)(29)(30)(31). Pharmacokinetic studies in mice and humans demonstrated that the concentration of I3C in plasma fell below the limit of detection within 1 h, whereas that of DIM remained detectable considerably longer after oral administration of I3C (10,11).…”

Section: Discussionmentioning

confidence: 95%

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Antiangiogenic Effects of Indole-3-Carbinol and 3,3'-Diindolylmethane Are Associated with Their Differential Regulation of ERK1/2 and Akt in Tube-Forming HUVEC

Kunimasa

Kobayashi

Kaji

et al. 2010

The Journal of Nutrition

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We previously reported that indole-3-carbinol (I3C), found in cruciferous vegetables, suppresses angiogenesis in vivo and in vitro. However, the underlying molecular mechanisms still remain unclear. Antiangiogenic effects of its major metabolite, 3,3'-diindolylmethane (DIM), also have not been fully elucidated. In this study, we investigated the effects of these indoles on angiogenesis and tested a hypothesis that I3C and DIM inhibit angiogenesis and induce apoptosis by affecting angiogenic signal transduction in human umbilical vein endothelial cells (HUVEC). We found that I3C and DIM at 25 micromol/L significantly inhibited tube formation and only DIM induced a significant increase in apoptosis in tube-forming HUVEC. DIM showed a stronger antiangiogenic activity than I3C. At the molecular level, I3C and DIM markedly inactivated extracellular signal-regulated kinase 1/2 (ERK1/2) and the inhibitory effect of DIM was significantly greater than that of I3C. DIM treatment also resulted in activation of the caspase pathway and inactivation of Akt, whereas I3C did not affect them. These results indicate that I3C and DIM had a differential potential in the regulation of the 2 principal survival signals, ERK1/2 and Akt, in endothelial cells. We also demonstrated that pharmacological inhibition of ERK1/2 and/or Akt was enough to inhibit tube formation and induce caspase-dependent apoptosis in tube-forming HUVEC. We conclude that both I3C and DIM inhibit angiogenesis at least in part via inactivation of ERK1/2 and that inactivation of Akt by DIM is responsible for its stronger antiangiogenic effects than those of I3C.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 95%

Antiangiogenic Effects of Indole-3-Carbinol and 3,3'-Diindolylmethane Are Associated with Their Differential Regulation of ERK1/2 and Akt in Tube-Forming HUVEC

Kunimasa

Kobayashi

Kaji

et al. 2010

The Journal of Nutrition

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“…The I3C inhibition of elastase enzymatic activity directly prevents cleavage of the CD40 member of the tumor necrosis factor receptor gene family, which causes CD40 signaling to switch from activating cell survival pathways to triggering anti-proliferative cascades in human breast cancer cells (20, 21). Relatively little is known about the responsiveness of human skin cancers to I3C beyond the observations that I3C increases the sensitivity to UV induced apoptosis and enhances cytotoxic responses in human melanoma (22, 23) and squamous cell carcinomas (24), respectively. Conceivably, the sensitivity of human melanoma cells to I3C may be to due to the expression and function of melanoma expressed indolecarbinol target proteins that can activate anti-proliferative signaling cascades and/or disrupt cell survival pathways.…”

Section: Introductionmentioning

confidence: 99%

The Antiproliferative Response of Indole-3-Carbinol in Human Melanoma Cells Is Triggered by an Interaction with NEDD4-1 and Disruption of Wild-Type PTEN Degradation

Aronchik

Kundu

Quirit

et al. 2014

Molecular Cancer Research

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Human melanoma cells displaying distinct PTEN genotypes were used to assess the cellular role of this important tumor suppressor protein during the anti-proliferative response induced by the chemopreventative agent indole-3-carbinol (I3C), a natural indolecarbinol compound derived from the breakdown of glucobrassicin produced in cruciferous vegetables such as broccoli and Brussels sprouts. I3C induced a G1-phase cell cycle arrest and apoptosis by stabilization of PTEN in human melanoma cells that express wild-type PTEN, but not in cells with mutant or null PTEN genotypes. Importantly, normal human epidermal melanocytes were unaffected by I3C treatment. In wild-type PTEN-expressing melanoma xenografts, formed in athymic mice, I3C inhibited the in vivo tumor growth rate and increased PTEN protein levels in the residual tumors. Mechanistically, I3C disrupted the ubiquitination of PTEN by NEDD4-1 (NEDD4), which prevented the proteasome-mediated degradation of PTEN without altering its transcript levels. RNAi-mediated knockdown of PTEN prevented the I3C induced apoptotic response; whereas, knockdown of NEDD4-1 mimicked the I3C apoptotic response, stabilized PTEN protein levels and down-regulated phosphorylated AKT1 levels. Co-knockdown of PTEN and NEDD4-1 revealed that I3C regulated apoptotic signaling through NEDD4-1 requires the presence of the wild-type PTEN protein. Finally, in silico structural modeling in combination with isothermal titration calorimetry analysis demonstrated that I3C directly interacts with purified NEDD4-1 protein. Implications This study identifies NEDD4-1 as a new I3C target protein, and that the I3C disruption of NEDD4-1 ubiquitination activity triggers the stabilization of the wild-type PTEN tumor suppressor to induce an anti-proliferative response in melanoma.

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“…Thus far, I3C has only been found to promote apoptosis in melanoma cell lines. In addition, I3C sensitized G361 melanoma cells to UVB radiation through decreased anti-apoptotic Bcl-2 expression [325]. Another study found that I3C induces apoptosis in SK-MEL-5 melanoma cells by down-regulation of MITF [326].…”

Section: Phytochemicals For the Prevention/treatment Of Melanomamentioning

confidence: 99%

Phytochemicals for the Management of Melanoma

Pal¹,

Hunt²,

Diamond³

et al. 2016

MRMC

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Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

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Indole-3-carbinol enhances ultraviolet B-induced apoptosis by sensitizing human melanoma cells

Cited by 42 publications

References 26 publications

Antiangiogenic Effects of Indole-3-Carbinol and 3,3'-Diindolylmethane Are Associated with Their Differential Regulation of ERK1/2 and Akt in Tube-Forming HUVEC

Antiangiogenic Effects of Indole-3-Carbinol and 3,3'-Diindolylmethane Are Associated with Their Differential Regulation of ERK1/2 and Akt in Tube-Forming HUVEC

The Antiproliferative Response of Indole-3-Carbinol in Human Melanoma Cells Is Triggered by an Interaction with NEDD4-1 and Disruption of Wild-Type PTEN Degradation

Phytochemicals for the Management of Melanoma

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