MITF-siRNA Formulation Is a Safe and Effective Therapy for Human Melasma

Xiang, Yong‐Bing; Zhao, Guohao; Zhang, Hongjie; Guan, Di; Meng, Rusong; Zhang, Yingyu; Qiu, Yang; Jia, Henming; Dou, Kejun; Liu, Chui; Que, Fangyuan; Yin, James Q.

doi:10.1038/mt.2010.263

Cited by 51 publications

(39 citation statements)

References 38 publications

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“…5C). MITF is crucial for the survival of melanoma cells, as evidenced by the findings that MITF depletion leads to a massive cell death (16,17). We noticed that MITF-decreased cells also had increased cleaved PARP and caspase-9 and decreased level of B-cell lymphoma-extra large (BCL-XL) (Fig.…”

Section: Identification Of Genomic and Expression Abnormalities In Humanmentioning

confidence: 76%

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Lin

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) downregulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatment of cancer cells with a unique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.

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Section: Identification Of Genomic and Expression Abnormalities In Humanmentioning

confidence: 76%

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Lin

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Stratum corneum-penetrating peptides have been some of the most promising topical constructs. Topical administration of hybrid MITF siRNA-peptide conjugates reduced MITF mRNA by 50% in mouse skin and reduced pigmentation in Chinese human subjects with facial melisma when the constructs were applied for 12 wk to their skin (35). Most recently, a skin-permeating and cell-entering peptide was shown to enhance siRNA delivery, leading to 43% knockdown of GAPDH protein in shaved BALB/c mouse skin at the maximal concentration tested, 10 μM (36).…”

Section: Discussionmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

356

288

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Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

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“…As described in the introduction, MITF is a key regulator of melanogenesis and a possible target for the treatment of hyperpigmentation diseases (6,7). Therefore, in the present study, it was hypothesized that the asiaticoside-dependent inhibition of melanogenesis could be regulated by MITF transactivation activity.…”

Section: A B a Bmentioning

confidence: 92%

“…Microphthalmia-associated transcription factor (MITF) transcriptionally regulates these key enzymes in melanocytes (5). Therefore, the regulation of MITF is central for hyper-or hypo-pigmentation diseases and for skin whitening for cosmetic purposes (6,7).…”

Section: Introductionmentioning

confidence: 99%

Asiaticoside, a component of Centella asiatica, inhibits melanogenesis in B16F10 mouse melanoma

Kwon

Bae

Kim

et al. 2014

Molecular Medicine Reports

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Abstract. Melanogenesis is the process of generating pigmentation via melanin synthesis and delivery. Three key enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1) and TRP2, metabolize melanin from L-tyrosine. Melanin synthesizing enzymes are regulated by microphthalmia-associated transcription factor (MITF). The titrated extract of Centella asiatica (TECA) contains the major components asiatic acid, asiaticoside and madecassic acid. The present study revealed that TECA reduces the melanin content in melanocytes. Moreover, the asiaticoside contained in TECA modulated melanogenesis by inhibiting tyrosinase mRNA expression. The decrease in tyrosinase mRNA levels was mediated through MITF. Uniquely, asiaticoside inhibited MITF by decreasing its DNA binding affinity. In conclusion, the results of the present study indicate that asiaticoside treatment may have beneficial effects in hyperpigmentation diseases or for skin whitening.

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MITF-siRNA Formulation Is a Safe and Effective Therapy for Human Melasma

Cited by 51 publications

References 38 publications

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Asiaticoside, a component of Centella asiatica, inhibits melanogenesis in B16F10 mouse melanoma

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