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Zhu et al. Function of Mcl-1 and its regulative relations with HCC

DRUG R&D FOR REGULATING MCL-1 OF HCC 1 to down-regulate the expression of Mcl-1 protein
and to induce the apoptosis of macrophage. In the
Drugs that down-regulate Mcl-1 research of HCC therapies, Yang et al. [99] found that
Cyclin-dependent kinase inhibitors a disintegrin and metalloproteinase 10 (ADAM10)
Flavopiridol is a semisynthetic compound that functions overexpression conferred resistance to doxorubicin-
as a CDK inhibitor though inhibiting CDKs and thus induced apoptosis in HCC, whereas the pretreatment
inducing cell cycle arrest at the G1 or the G2/M transition with the PI3K inhibitor LY294002 significantly enhanced
point. [92] In a recent study, flavopiridol augmented TNF- doxorubicin-induced apoptosis and diminished the
related apoptosis-inducing ligand (TRAIL) sensitivity of Mcl-1 expression in ADAM10-overexpressing Huh7
human HCC cells by up-regulation of TRAIL receptors cells. And also LY294002 could down-regulate the
and down-regulation of survivin, FLICE-inhibitory expression of Mcl-1 rapidly in HCC cells and increase
protein and Bcl-xL. [93] Flavopiridol has also been shown the sensitivity of HCC cells to chemotherapeutics. [35]
to induce apoptosis in a P53-independent manner and
to down-regulate XIAP, Mcl-1, Bcl-2, survivin in kinds MEK/ERK signaling inhibitors
of cancer cells. [94,95] Sorafenib actually inhibits multiple other kinases. It is the
first and only orally administered drug to treat advanced
Another CDK inhibitor, as mentioned above, is HCC. One of the molecular mechanisms of sorafenib in
ibulocydine - a novel isobutyrate prodrug inhibitor of HCC cells is that sorafenib induces apoptosis by reducing
CDK7/9. In comparison, ibulocydine inhibited the growth elF4E phosphorylation and blocking the initiation of
of HCC cells more effectively than other CDK inhibitors Mcl-1 translation. [100] Chen et al. [47] demonstrated
via prolonged inhibition of CDK7/9 leading to induction of that sorafenib downregulated phospho-STAT3 and
apoptosis by down-regulating the cellular levels of anti- subsequently reduced the expression levels of STAT3-
apoptotic proteins such as Mcl-1 and XIAP. Besides, data related proteins including Mcl-1 in a dose- and time-
from human HCC xenografts indicated that ibulocydine dependent manner in TRAIL-treated HCC cells.
selectively induced apoptosis but has no cytotoxic effects
on normal tissues. Consequently, ibulocydine is a strong Antisense oligonucleotide treatment
candidate for the treatment of HCC. Antisense oligonucleotide (ASO) [10] is a kind of
[84]
synthetic oligonucleotides fragment expressed by
Deubiquitinase inhibitors antisense expression plasmid. Recently, it has been
Mcl-1 is degraded rapidly in the cell via a proteasome- found that Mcl-1 ASO could downregulate Mcl-1
dependent pathway, whereas deubiquitinases (DUBs) efficiently in various tumor cells and animal models.
are capable of removing ubiquitin from ubiquitinated According to ASO treatment as monotherapy in the
Mcl-1 to rescue Mcl-1 from degradation. WP1130, a HCC cell lines HepG2 and Snu398, the result showed
small molecule that was initially identified as JAK and that ASO targeting Mcl-1 specifically downregulated
STAT inhibitors, can also inhibit activity of DUBs. And Mcl-1 protein expression and led to significant dose
it has been demonstrated that DUBs ubiquitin-specific and time dependent single agent activity in HCC cells
protease 9X (DUB USP9X) was one of the proteins characterized by increased apoptosis and decreased
to co-immunoprecipitates with Mcl-1. [96] In a recent cell viability. And Upon combination with cisplatin,
study, it has been found that combined treatment Mcl-1 ASO revealed a significant chemosensitizing
with WP1130 sensitized HCC cells to doxorubicin via effect. [10] However, there is no report about Mcl-1 ASO
USP9X-depedent P53 degradation. [97] treatment used in clinic.

STAT protein inhibitors BH3 mimetics
As mentioned previously, STAT could regulate Mcl-1 BH3 mimetics mainly play a part through the interaction
at transcriptional level, thus attenuating the activity of proteins to inhibit Mcl-1’s function. As discussed,
of STAT protein by agents is a fine choice to down- there was a surface-exposed hydrophobic groove
regulate the expression of Mcl-1 proteins. Surprisingly, contributing to the anti-apoptosis function of Mcl-
ethanol extracts from Sedum sarmentosum have been 1 [Figure 2]. [17] Consequently, BH3 mimetics were
reported to inhibit STAT-3 signaling, down-regulate Mcl- designed to fit into the hydrophobic groove and block
1 and Bcl-2 expressions, and finally inhibit proliferation Mcl-1’s ability to bind pro-apoptotic proteins, inhibiting
of HepG2 cells, and induce HepG2 cells apoptosis. [98] the anti-apoptosis function of Mcl-1. ABT-737, a small-
molecule cell-permeable Bcl-2/Bcl-XL antagonist,
PI3K/Akt signaling inhibitors is a novel cancer therapeutic agent because it
LY294002 functions as a PI3K/Akt signaling inhibitor potently induces apoptosis in certain cancer cells.
which is capable of repressing the activation of AKT- Nevertheless, owing to low affinity with Mcl-1, ABT-
Hepatoma Research ¦ Volume 3 ¦ July 06, 2017 135