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Abe et al. J Cancer Metastasis Treat 2020;6:51 I http://dx.doi.org/10.20517/2394-4722.2020.117 Page 11 of 15

benefits for the treatment of heart failure. These preliminary studies support the causative involvement of
GSK3b in doxorubicin-induced cardiotoxicity and occurrence of congestive heart failure. They also provide
new insights into the underlying mechanisms of this fatal cardiac complication and suggest a possible
therapy [Figure 2].

Recently, we reviewed the benefits of targeting GSK3b for various cancer therapy-induced adverse events
including immunosuppression, hematotoxicity, central, and peripheral neuropathy, and opioid-induced
[30]
analgesic tolerance and withdrawal syndrome [Figure 2]. Increasing evidence has indicated new roles
for GSK3b in the repair of DNA base excision and double-strand breaks and in the inhibition of apoptosis
via NF-κB activation, thus highlighting the potential of GSK3b inhibitors for inducing chemo- and radio-
sensitization in various cancer types [135] . In summary, targeting of GSK3b during standard chemotherapy
for bone and soft tissue sarcomas is expected to provide the dual benefits of enhancing cytocidal efficacy
while reducing the cardiotoxicity of doxorubicin [Figure 2].

CONCLUSION
GSK3b sustains the progression of aggressive bone and soft tissue sarcomas including osteosarcoma,
embryonal and alveolar rhabdomyosarcomas, synovial sarcoma, and fibrosarcoma, and potentially also
UP sarcoma. Laboratory studies have demonstrated therapeutic effects of GSK3b inhibition against these
sarcoma types, as well as against therapy-associated adverse effects including defects in healthy tissues
following surgery and doxorubicin-induced cardiotoxicity. The accumulated evidence has provided new
insights into the causative role of GSK3b in bone and soft tissue sarcomas, thus reinforcing GSK3b as a
potential therapeutic target.

DECLARATIONS
Acknowledgments
We acknowledge Dr. Barry Iacopetta (University of Western Australia) for critical review and editing of the
manuscript.

Authors’ contributions
Made substantial contributions to conception and design of this review: Minamoto T
Original draft preparation: Abe K, Shimozaki S
Writing, review, and editing of manuscript: Yamamoto N, Tsuchiya H, Minamoto T
Performed literature research: Abe K, Shimozaki S, Domoto T

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology-Japan and from the Japan Society for the Promotion of Science (to Abe K,
Yamamoto N, Tsuchiya H, and Minamoto T).

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

Ethical approval and consent to participate
Not applicable.