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

737-mediated apoptosis signaling was inhibited in HCC patients with advanced HCC, which indicates S-1 is a
cells due to the elevated expression of Mcl-1 which potential candidate for antitumor agent.
may contribute to HCC resistance to ABT737. [101,102]
Consequently, it is unlikely to be effective as a single CONCLUSION
agent in solid tumors and thereby a great many
research about combining ABT-737 with other agents With highly expressed Mcl-1, HCC cells tend to
to abolish the resistance has emerged recently such escape from apoptosis and thus proliferate at an
as norcantharidin, celastrol, etc. [103,104] increasingly high speed. Mcl-1 is a critical survival
factor for malignant tissues of HCC and its expression
Polyphenols derivatives is regulated via multiple mechanisms. Hence, it is a
The mother nucleus structure of polyphenols derivatives promising target for HCC treatment. Over the past
has polyhydroxyphenol. Gossypol as a typical BH3 several decades, there has been significant progress
mimetic that inhibits the Bcl-2 anti-apoptotic proteins towards relevant molecular interacting with Mcl-1. On
Bcl-2, Bcl-XL, and Mcl-1 by binding to them. [105] the one hand, Mcl-1’s expression in HCC is regulated
Because of the ability to target Mcl-1, gossypol shows at transcriptional by a variety of cytokines and signaling
toxicity against variety of cancer types in comparison pathways, including the P38/MAPK, PI3K/AKT, STAT,
to ABT-737. Since it was shown that HCC cells P53, ERK, JNK, Wnt/β-catenin, Notch signaling ways.
were relatively resistant to Bcl-2 inhibitors, then co- On the other hand, the role of microRNAs in Mcl-1
treatment of Bcl-2 inhibitor (-)-gossypol and Hsp90 regulation has been highlighted at the translational
inhibitor 17-AAG attenuated (-)-gossypol-induced level and multiple phosphorylation sites in Mcl-1’s
protective autophagy by inhibiting ERK-mediated Bcl- PEST region regulate Mcl-1 expression at post-
2 phosphorylation and downregulated (-)-gossypol- translational level. Other Mcl-1 interacting proteins
such as Mule, CDK1, CDK2, PCNA, TCTP, etc. also
triggered Mcl-1 accumulation by suppressing Mcl-1 involve in Mcl-1 regulation through interaction with it.
Thr163 phosphorylation. [70] Apogossypolone (ApoG2) According to these molecular mechanisms, numerous
was the first derivative of gossypol for the potential of chemotherapeutic agents have been reported to
non-specific reactivity related to the 2 aldehyde groups decrease the level of Mcl-1 towards HCC treatment
in gossypol. [106] In order to investigate the in vitro and including agents not specifically targeting Mcl-1 but
in vivo activities and related mechanism of ApoG2 involving downregulation of Mcl-1 and those drugs
against HCC, Mi et al. [107] found that the ApoG2 induced targeting Mcl-1 directly. Thereinto, BH3 mimetics are
apoptosis in SMMC-7721 cells by downregulation of the most studied among all the chemotherapies. Of
anti-apoptotic proteins Bcl-2, Mcl-1, and Bcl-XL and note, HCC with high levels of Mcl-1 are resistant to
up-regulation of pro-apoptotic protein Noxa, which apoptosis induction by some compounds, posing a
indicated ApoG2 was a potential pan Bcl-2 family major problem for its potential utility. Thus, combination
protein inhibitor, targeting Bcl-2, Mcl-1, and Bcl-XL, of multiple targets agents for HCC chemotherapy,
and inducing apoptosis in HCC. Moreover, several production of good drug delivery system, and designing
gossypol analogues arose to inactivate Mcl-1 such as novel interventions specifically targeting Mcl-1 will be a
TM-1206, [108] BI-33 [109] and TM-179. [110] major tendency in the future.

Indole dipyrrole derivatives Authors’ contributions
Obatoclax is a synthetic indole dipyrrole derivative Design and performing the research, manuscript
derived from prodigiosin and acts as a BH3 mimetic review: Y.M. Zhang
which binds the anti-apoptotic Bcl-2 proteins, releases Manuscript drafting: M. Zhu
proapoptotic proteins and thus triggers caspase
activation. And SC-2001 was originally derived from Financial support and sponsorship
the Mcl-1 inhibitor obatoclax, that was suggested
better antitumor effects than obatoclax in HCC cell This work was supported by the National Natural
lines, including HepG2, PLC5 and Huh-7. [111] Science Foundation of China (Grant no. 81370088),
the Fundamental Research Funds for the Central
Acenaphthene heterocyclic derivatives Universities of Zhuizong.
S-1 (one mixed formulation containing 5-FU prodrug
and dihydropyrimidine dehydrogenase inhibitor) Conflicts of interest
inhibits both Bcl-2 and Mcl-1 and is capable of There are no conflicts of interest.
disturbing interaction between Mcl-1 and Bak, resulting
in apoptosis. [112] Furuse et al. [113] reported that S-1 Patient consent
was effective and had an acceptable toxicity profile in Not applicable.
136 Hepatoma Research ¦ Volume 3 ¦ July 06, 2017