Didymin: an orally active citrus flavonoid for targeting neuroblastoma

Abstract

Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases. Didymin is a citrus-derived natural compound that kills p53 wild-type as well as drug-resistant p53-mutant neuroblastoma cells in culture. In addition, orally administered didymin causes regression of neuroblastoma xenografts in mouse models, without toxicity to non-malignant cells, neural tissues, or neural stem cells. RKIP is a Raf-inhibitory protein that regulates MYCN activation, is transcriptionally upregulated by didymin, and appears to play a key role in the anti-neuroblastoma actions of didymin. In this review, we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2, PKCs, Let-7 micro-RNA, and clathrin-dependent endocytosis by Raf-dependent and -independent mechanisms. In addition, we will discuss studies supporting potential clinical impact and translation of didymin as a low cost, safe, and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma.

LC-MS Analysis of Phytocomponents in the Methanol Extract of Piper Sarmentosum Leaves

“…36 Didymin is a dietary flavonoid glycoside known to have antioxidant properties. 29 It had been shown to be an effective oral agent for refractory neuroblastoma 37 and a neuroprotective agent 38 in animal models. Hesperidin is one of the flavanoids in many Rutaceae families' for example; Citrus spp and Poncirus trifoliate.…”

The role of rutin and diosmin, two citrus polyhydroxyflavones in disease prevention and treatment

“…Diosmin (diosmetin 7-O-rutinoside) ( Figure 1) was first isolated from leaves of Scrophularia nodosa L., (Scrophulariaceae) in 1925. Later studies revealed that diosmin occurred abundantly in the pericarp (Bogucka-Kocka et al, 2013;Patel et al, 2013;Singhal et al, 2017;Yao et al, 2018) but also in the pulp and juice of different citrus fruits species (e.g., Citrus sinensis, C. clementina, C. aurantium, C. limon, C. aurantifolia and C. bergamia (Gattuso et al, 2007). A comparative study analyzing 42 Citrus species showed specific differences in levels of diosmin in pericarp, pulp and juice throughout the different species.…”

Recent Trends in Potential Therapeutic Applications of the Dietary Flavonoid Didymin

“…Didymin is commonly found in citrus fruits and campanula, including mandarin, bergamot, orange, Origanum , and Vulgare Duanxueliu . Due to its high content in citrus and easy extraction, didymin has been recognized as an inexpensive, safe and effective oral drug that does not cause toxicity to normal tissues [ 16 ]. The therapeutic potential of didymin with anti-oxidant in promoting health is drawing more attention in recent five years.…”