Page 678 - Read Online

Page 10 of 15 Abe et al. J Cancer Metastasis Treat 2020;6:51 I http://dx.doi.org/10.20517/2394-4722.2020.117

Figure 3. Therapeutic efficacy of GSK3b inhibitors (AR-A014418 and SB-216763) against human osteosarcoma cell orthograft tumors in
the knee joints of mice [46] (left panels) and schematic representation of the hypothetical triple benefits of GSK3b inhibitors: anti-tumor
effect, reduction of post-surgery tissue defect, and bone preservation (right panels). Dotted lines in the middle two panels indicate the
area of orthograft tumors. GSK3b: glycogen synthase kinase 3b; DMSO: dimethyl sulfoxide (diluent for GSK3b inhibitors)

1], the targeting of GSK3b in musculoskeletal sarcomas may have three therapeutic advantages: a direct
therapeutic effect against the tumor, reduction of the defect in unaffected tissue following surgical resection
of the tumor, and preservation and repair of adjacent healthy tissues [Figures 2 and 3].

Doxorubicin-induced cardiotoxicity
Doxorubicin is an anthracycline derivative that comprises the amino sugar daunosamine linked to a
hydroxy anthraquinone aglycone [125] . It is the backbone of first line chemotherapy regimens for most bone
[7,8]
and soft tissue sarcomas . Like all anthracyclines [125] , its antitumor effects are mediated by interaction
with DNA, generation of oxidative stress, and inhibiting the functions of topoisomerase II in maintaining
DNA tangles and supercoils. Resistance to treatment and drug-induced cardiotoxicity are the major
concerns with doxorubicin treatment of patients with advanced bone and soft tissue sarcomas. High
cumulative dosage of doxorubicin frequently leads to cardiac toxicity and occasionally to irreversible
congestive cardiac failure, with younger patients being the most susceptible [126] . This devastating adverse
event is associated with disruption of mitochondrial fusion and mitochondrial fragmentation in
cardiomyocytes, resulting in impaired mitochondrial function [127] . While the exact molecular mechanism
of cardiotoxicity has yet to be clarified, the targeting of impaired mitochondrial dynamics and function
is a potential strategy for the prevention and treatment of this adverse cardiac event [127,128] . Many studies
have investigated the cardiomyoprotective effect of various compounds derived from phytochemicals such
as phenols, terpenoids, quinones, alkaloids, polysaccharides, carotenoids, lignans, and others. Although
these phytochemicals are expected to serve as templates for drug development, to date none has yet proven
clinically effective in the prevention of doxorubicin-induced cardiotoxicity [128] .

The possibility of using GSK3b as a therapeutic target for cardiomyocyte protection has attracted
considerable attention [129-132] . Earlier studies reported a causative role for GSK3b in the necrosis and
apoptosis of cardiomyocytes [129] and a protective role against cardiac fibrosis [130] . GSK3b inhibition
protects cardiomyocytes from necrosis via opening the mitochondrial permeability transition pore. It
also protects cardiomyocytes from apoptosis induced by pressure overload or by repeat ischemia and
perfusion. This is associated with reduced phosphorylation of p53, heat shock factor-1, and myeloid
cell leukemia sequence-1, and inhibition of Bax translocation [129] . Subsequent studies showed the effect
of targeting GSK3b on the maintenance of myocardial homeostasis, as well as the therapeutic effects of
GSK3b inhibition against diabetes-associated myocardial injury and experimentally induced myocardial
infarction [131,132] . A recent study demonstrated that GSK3b inhibition ameliorates triptolide-induced acute
cardiac injury in rodents by desensitizing the mitochondrial permeability transition [133] . Another study
S9
showed that phosphorylation-mediated inactivation of GSK3b (pGSK3b ) is associated with the alleviation
of doxorubicin-induced inflammation, oxidative stress, and apoptosis in H9c2 rat cardiomyocytes [134] . This
was achieved by treatment with Yangxin granules, a Chinese herbal medicine confirmed to possess clinical