Page 33 - Read Online

Page 12 of 16 Merhi et al. J Cancer Metastasis Treat 2021;7:42 https://dx.doi.org/10.20517/2394-4722.2021.80

[94]
humans have demonstrated oral bioavailability of HF . However, two aspects limit the pharmacological
use of purified HF, which concern: (1) its poor solubility and instability [30,95] ; and (2) its interference with
other therapeutic drugs via activation of liver CYP450 enzymes involved in the metabolism of
pharmaceutical drugs (notably, CYP3A4) [94,96,97] . Oral administration by healthy volunteers of SJW extracts
(300-2700 mg containing 14.8-70 mg of HF) results in the detection of 0.15-1.45 μg/mL (0.28-2.68 μM) HF
concentrations in blood 3 h after absorption [94,98-100] . An SJW treatment period of 12.5-21 days using high HF
extracts (> 27 mg/day) demonstrates a significant CYP3A induction . Altogether, these data strongly
[97]
suggest that the maximal concentration of HF in blood should not exceed 0.3 μg/mL (0.56 μM) to reduce the
frequency of drug interactions. With regard to our data obtained in vitro, it remains to examine whether or
not apoptosis and inhibition of secretion of AML cells in vivo can be triggered by a such low dose of HF. In
the last years, various chemical derivatives of HF have been developed with improved stability and
solubility, in the hope of removing HF drug metabolism stimulatory activities without affecting its
antitumor properties. Thus, HF-DCHA, tetrahydro-HF-DCHA, octahydro-HF-DCHA, and O-(carboxy
methyl)-HF have been shown to retain the antitumor and antiangiogenic properties of HF without inducing
toxicity in laboratory animals [28,68,101,102] . Whether these HF derivatives retain the antileukemic properties of
parental HF in vitro in AML primary cells and in experimental animals should be established. In parallel,
the effects of these analogs on CYP3A activity have yet to be evaluated on healthy volunteers. Ongoing
therapeutic strategies involve encapsulation of HF into polymeric nanoparticles for overcoming hurdles that
hamper the bioactivity and bioavailability of the drug [103-106] . In conclusion, although further studies are
undoubtedly required, all these data highlight that HF and its derivatives deserve further study to evaluate
them in association with chemotherapy in the treatment of AML.

DECLARATIONS
Acknowledgments
The authors thank Fanny Fava (Hôpital Saint-Antoine, Paris, France) for her expert technical assistance.
This work is dedicated to Jean-Pierre Kolb, a pionner in the research on antitumoral activity of HF in CLL.

Authors’ contributions
Conceptualization: Merhi F, Bauvois B
Formal analysis: Merhi F, Tang R, Bauvois B
Investigation: Merhi F, Bauvois B
Methodology: Tang R, Merhi F, Bauvois B
Resources: Legrand O
Writing, review and editing: Merhi F, Tang R, Legrand O, Nguyen-Khac F, Susin SA, Bauvois B
All authors have read and agreed to the published version of the manuscript.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by the French National Institute of Health and Medical Research (INSERM). This
research received no external funding.

Conflicts of interest
All authors declared that there are no conflicts of interest.