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Merhi et al. J Cancer Metastasis Treat 2021;7:42 https://dx.doi.org/10.20517/2394-4722.2021.80 Page 3 of 16

Figure 1. Hyperforin (HF) is a bio-active acylphloroglucinol abundantly present in the apical flowers of St John’s wort (SJW) Hypericum
perforatum L. SJW is a perennial flowering plant. HF is the primary active compound responsible for both the antidepressant and the
anti-inflammatory properties of SJW. The chemical structure of HF is C H O (536 g/mol).
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4
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is graft-versus-host disease . The conventional chemotherapeutic approach for AML patients is based on a
[4]
treatment combining an anthracycline with cytarabine [35-37] . However, a majority of patients with AML are
refractory to primary therapies or relapse later [35-37] . Both resistance and relapse are due to the heterogeneity
of the disease, where high variability both among and within individual patients exist [35-37] . This underscores
the need for alternative treatment options for AML patients, with increased tolerability and improved
efficacy. Today, alternative strategies for the treatment of newly diagnosed AML patients include a new
liposomal formulation of cytarabine and daunorubicin or the combination of venetoclax (a BH3 mimetic
that inhibits the survival function of the B-cell lymphoma-2 anti-apoptotic protein) with hypomethylating
agents or a low dose of cytarabine [36-38] . Unfortunately, these therapies are often still accompanied by adverse
effects or favored mutations associated to drug resistance [36-38] . Therefore, novel therapies are needed to
overcome resistance to these drugs, and the identification of new drugs in AML therapy is of great interest.

Increased BM angiogenesis in AML correlates with high levels of VEGF-A [39,40] . BM blasts from patients with
AML express and secrete VEGF-A [39-42] . The transcript and protein levels of VEGF-A are highly variable in
circulating AML cells from pediatric patients . The enhanced VEGF-A levels observed in plasma from
[43]
AML patients might be explained as the expression of VEGF-A release from blood AML cells, and it appears
to be associated with worse event-free survival and poor overall survival in AML . In contrast to normal
[44]
BM immature CD34 progenitor cells, BM AML blasts express MMP-2 and MMP-9 transcripts and release
+
detectable levels of MMP-2 and MMP-9 proteins [45-47] . Similarly, blood AML cells express and secrete MMP-
2 and MMP-9 . To the best of our knowledge, there are no literature data reporting the co-expression of
[48]
VEGF-A and MMP-2/9 in circulating AML blasts. In this study, we first analyzed the expression status of
these factors in myeloid blasts from peripheral blood as a function of the latter’s French-American-British
(FAB) subtype (M0, M1, M2, M3, M4, and M5). In addition, we investigated the ability of HF to exhibit
anti-cancer activity in AML disease through the modulation of AML cell survival process and secretion of
MMP-2/9 and VEGF-A. Understanding HF’s anti-leukemic activity in AML may provide a new model for
the treatment of this disease.

METHODS
Patients, AML samples, and cell cultures
Peripheral blood was collected from 45 patients with AML according to standard clinical criteria and the
+ [49]
+
FAB Committee’s cytological criteria (≥ 80% peripheral blood AML blasts CD33 CD13 ) . The biological
and clinical characteristics of AML patients are listed in Table 1. Bone marrow (BM) samples were collected