Page 32 - Read Online

Merhi et al. J Cancer Metastasis Treat 2021;7:42 https://dx.doi.org/10.20517/2394-4722.2021.80 Page 11 of 16

A production; and (2) apoptosis in primary AML cells. However, to what extent are apoptosis and secretion
interdependent or related? A previous study showed that the stable dicyclohexylammonium salt of HF (HF-
DCHA, 0.5 μM) inhibits MMP-2 release by two human epithelial cell lines (HT-1080 and SK-N-BE), while
apoptosis in these cells is induced at concentration 16-fold higher (IC ≥ 8 μM), suggesting that HF-DCHA
induces two separate events in these tumor models . The effect of HF at ≤ 2 μg/mL on MMP-2/9 and
[68]
VEGF-A release remains to be assessed in AML cells. Furthermore, the decreased production of these
hemoregulators might result from the apoptotic process. Conversely, the inhibition of MMP-2/9 and
VEGF-A might impact the survival of AML cells. Indeed, VEGF-A signaling (via PI3K/Akt activation)
favors autocrine AML cell proliferation, survival, and chemotherapy resistance [69,70] . Moreover, proMMP-2
and proMMP-9 have the ability to directly activate signaling pathways modulating cell survival, migration,
[8]
and angiogenesis . For example, the binding of proMMP-9 to its docking receptors α4β1 integrin and CD44
induces an intracellular signaling pathway (STAT3/Lyn/Mcl-1) that favors the survival of circulating
[71]
chronic lymphocytic leukemia cells . Similarly, the binding of proMMP-2 or proMMP-9 to the integrins α
Lβ2 and αMβ2 induces the migration of human AML cell lines . Although AML cells from the majority of
[72]
patients (at diagnosis or relapse) express chains of integrins and CD44 , the potential roles of proMMP-2/9
[73]
in AML cell survival remain to be shown. Alternatively, HF might induce two simultaneous but distinct
events (apoptosis and secretion inhibition) in AML cells. Due to its physicochemical properties, HF is easily
incorporated into the membrane lipid bilayer, where it can function as a protonophore . Lipid rafts
[74]
modulate Akt/BAD signaling in cancer cells [75,76] and regulate exocytosis/endocytosis pathways [77-80] . Whether
HF disrupts lipid rafts in AML cells, which in turn simultaneously lead to cell apoptosis (through activation
of Akt1/BAD) and blockade of secretion of MMP-2/9 and VEGF-A (through exocytosis inhibition) remains
to be established. In view of this possibility, HF could join the family of natural compounds (including
quercetin, epigallo catechin-3-gallate, resveratrol, and genistein) that induce apoptosis of tumor cells and
block cytokine secretion through alteration of lipid rafts [75,76,81-84] .

In conclusion, among the search for novel therapeutics for AML, there is a need for the development of
drugs that block angiogenesis associated with the AML disease. The inhibition of VEGF-A and/or MMP-2/9
may provide a therapeutic benefit in AML. Antiangiogenic strategies have sought to target the MMPs’
[85]
catalytic activity . The failure of MMP inhibitors as cancer drugs in the clinic may be explained by their
lack of selectivity towards MMPs (including MMP-2/9). New approaches are focusing on more selective
MMP inhibitors that target motifs outside the active site (the “exosite”) of individual MMPs; these newly
designed inhibitors include peptides that block exosite-mediated cell surface interactions and function-
blocking anti-MMP antibodies [85-87] to target proMMP-9-mediated cell migration in vitro [88-90] . To date, no
efficient therapy based on MMP inhibition has been made available for targeting angiogenesis in cancers
including AML, and new strategies are currently developing MMP-responsive drug delivery vehicles .
[87]
Studies with various VEGF inhibitors are currently underway in a number of tumors [1,91,92] . Bevacizumab, a
humanized monoclonal antibody, binds to all circulating forms of VEGF, and thus it prevents VEGF
binding to VEGF receptors. In addition to bevacizumab, other drugs have been reported to inhibit the
binding of VEGF to its receptors (aflibercept) or block the signaling pathway mediated by VEGF receptors
(ramucirumab, pazopanib, and axitinib) [1,91] . Bevacizumab treatment of AML patients with
refractory/relapsing disease reduced VEGF expression at the level of BM but failed to show any significant
clinical antileukemic activity . Other clinical trials incorporating antibodies against VEGF or VEGF
[36]
receptors-2 have not produced results supporting a significant clinical benefit . These inhibitors share
[36]
toxicity and other side effects [1,91,92] . Therefore, the development of new efficient antiangiogenic therapies is
necessary. Utilization of natural compounds can be an alternative and/or an additional possibility to inhibit
tumor development and associated angiogenesis [75,76,82-84] . By blocking in vitro the proliferation of primary
blood endothelial cells, and reducing tumor vascularization and tumor-induced lymphangiogenesis in rat
models [30,32,93] , HF could already be qualified as a putative antiangiogenic agent. Pharmacokinetics studies in