Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

Abstract

Biflavonoids are divided in two classes: C–C type compounds represented by the dimeric compound amentoflavone and C–O–C-type compounds typified by hinokiflavone (HNK) with an ether linkage between the two connected apigenin units. This later sub-group of bisflavonyl ethers includes HNK, ochnaflavone, delicaflavone and a few other dimeric compounds, found in a variety of plants, notably Selaginella species. A comprehensive review of the anticancer properties and mechanism of action of HNK is provided, to highlight the anti-proliferative and anti-metastatic activities of HNK and derivatives, and HNK-containing plant extracts. The anticancer effects rely on the capacity of HNK to interfere with the ERK1-2/p38/NFκB signaling pathway and the regulation of the expression of the matrix metalloproteinases MMP-2 and MMP-9 (with a potential direct binding to MMP-9). In addition, HNK was found to function as a potent modulator of pre-mRNA splicing, inhibiting the SUMO-specific protease SENP1. As such, HNK represents a rare SENP1 inhibitor of natural origin and a scaffold to design synthetic compounds. Oral formulations of HNK have been elaborated to enhance its solubility, to facilitate the compound delivery and to enhance its anticancer efficacy. The review shed light on the anticancer potential of C–O–C-type biflavonoids and specifically on the pharmacological profile of HNK. This compound deserves further attention as a regulator of pre-mRNA splicing, useful to treat cancers (in particular hepatocellular carcinoma) and other human pathologies.

Biflavonoids from Selaginella doederleinii as Potential Antitumor Agents for Intervention of Non-Small Cell Lung Cancer

“…Natural biflavonoids, such as amentoflavone, bilobetin, ginkgetin, isoginkgetin, taiwaniaflavone, morelloflavone, delicaflavone and hinokiflavone isolated from Selaginella sp., Ginkgo biloba , Garcinia sp., and several other species of plants, are known to link the individual flavones to each other by direct C-C or C-O-C bonds [ 5 ]. During our continuous effort to discover active ingredients of the air-dried whole herbs of S. doederleinii , a series of dimeric flavones, including four previously undescribed biflavonoids, were isolated.…”

“…The traditional roles of biflavones in cancer therapy can be defined with respect to the inhibition of metabolism-related processes/pathways, enzymes or proteins, especially for apoptosis induction mechanisms [ 5 ]. Therefore, it is pertinent to evaluate the effect of biflavones on different proteins or mechanisms that lead to cell apoptosis in cancer cells.…”

“…It is well known that diverse bioactive secondary metabolites derived from plants provide a natural source of novel agents with distinct pharmaceutical activities. Natural biflavonoids are known to link the individual flavones to each other by direct C-C or C-O-C bonds, forming dimeric structures capable of having multiple therapeutic benefits [ 4 , 5 ]. Meanwhile, it has been reported that natural bioflavonoids have promising therapeutic effects on metabolic-, cardiovascular-, and cognition-related diseases, including cancer [ 5 ].…”

Origin and Function of Structural Diversity in the Plant Specialized Metabolome

“…Combinatorial coupling between a flavonoid semiquinone radical and a phenylpropanoid radical, such as coniferyl alcohol, forms a flavonolignan [111,112]. Combinatorial radical-radical coupling among flavones, flavonols, dihydroflavonols, flavanones, isoflavones, aurones and chalcones forms bi-, tri-, and tetraflavonoids [113][114][115][116][117][118][119][120][121]. Because the radical can be delocalized along the flavonoid conjugated system, various C-C or C-O-C linkage types are produced.…”

“…In certain cases, dimerization may have led to new functionalities. Biflavonoids have been mainly studied for their strong cytotoxic activity, suggesting a defensive role against herbivores in plants [ 119,122,123]. It is not known if the coupling occurs in a directed way, guided by a dirigent protein, in analogy with lignan biosynthesis, and also demonstrated for the synthesis of the phenolic terpenoid (+)-gossypol in cotton (Gossypium sp.)…”