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Page 14 of 23 ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71

like celecoxib decreased the rate of adenocarcinomas, markedly lowering angiogenesis parameters including
VEGF, MMP-2, MMP-9 and MCP-1 levels [174,183] . More importantly, inhibiting COX-2 with celecoxib was
found to block the PGE2-induced tumor repopulating capacity, which otherwise promoted chemoresistance
in bladder cancer xenografts [184] as well as CSC expansion and metastasis in colorectal cancer models [171] .

The role of COX-2 in CSC survival and repopulation after therapy has been reviewed elsewhere [185] , such
that it has become clear that inhibiting COX-2 is an effective method for preventing treatment failure due
to tumor repopulation. Moreover, celecoxib, as a selective COX-2 inhibitory drug, has also been reported to
promote the apoptosis of colon cancer cells [186] . The prostaglandin, PGE2 produced by COX-2 activates pro-
survival pathways preventing apoptosis of colon cancer cells [187] (reviewed in [168,188] ). Celecoxib, by inhibiting
COX-2 facilitates the activation of various apoptotic pathways in colorectal cancer cells, including p53, p38
and BAX pathways [189] .

Another aspect of the prostaglandins produced by COX-2 activity is that some, such as PGE2, are pro-
inflammatory cytokine-like factors that modulate the anticancer immune response [190] . Celecoxib’s
anticancer inhibitory effects (resulting from lower prostaglandin levels) also include promoting an enhanced
immune response. Thus, celecoxib inhibition of COX-2 prevents the switching from a Th1 to a Th2 immune
response, where Th2 would be more favorable to cancer cell survival. The immune response switch to Th2
is induced by increased levels of COX-2 which also leads to decreased production of the NF-κB activated
cytokines that would otherwise induce Th1 proliferation, including interferon gamma (IFN-γ), tumour
necrosis factor-alpha, and IL-2. Moreover, COX-2 activity promoted expression of cytokines including IL-
6, IL-4, and IL-10 which preferentially activate Th2 type immune responses [191] , thereby enabling the cancer
cells to evade the host immune system.

Tumor-associated COX activity in a mouse melanoma model driven by oncogenic mutation in Braf (similar
to the situation in human melanoma) was shown to be a key suppressor of type II IFN (IFN-γ) and T cell-
mediated tumor elimination, inducing an inflammatory signature more typically associated with cancer
progression [192] . COX-dependent immune evasion was also shown to be critical for tumor growth in a range
of models including melanoma, colorectal, and breast cancers [192] . Notably, tumor immune escape could
be reversed by a combination of an immune checkpoint blockade inhibitor together with COX inhibitors.
Hence, the COX-2/PGE pathway can promote tumor growth, survival and evasion of the immune response
and highlights the importance of using NSAIDs such as celecoxib to inhibit the COX-2/PGE based activities
in tumors.

We have shown that celecoxib has a fourth component to its anticancer function based on direct effects in
killing cancer cells by targeting their mitochondria to increase the respiratory substrate driven production of
reactive oxygen species such as superoxide, thereby activating the intrinsic apoptotic pathway [23,193] . Although
many of the NSAIDs show similar properties and ability to act as cytotoxic anticancer drugs (reviewed
in [194] ), celecoxib was found to be by far the most outstanding [23,193] and was highly effective at inhibiting
growth of triple negative breast cancer spheroids [195] . In this regard, in many animal models of cancer,
celecoxib has been shown to chemosensitize cancer cells in a synergistic manner to enhance the cytotoxic
effects of commonly used chemotherapies, such as the anthracycline drugs doxorubicin and epirubicin [196-200]
and platinum-based chemotherapies [164,199,201-206] . In murine models of colorectal cancer, synergistic anticancer
effects were obtained by combining celecoxib with the common CRC chemotherapeutic drug, 5-fluorouracil
[207]
(5-FU) or with oxaliplatin [208] .
In human hepatomas, Chu et al. [209] showed that celecoxib promoted death of the CSC population and
suppressed stemness and progression by up-regulating the tumor suppressor function of the tyrosine
phosphatase, PTEN. In related studies [84,210] , celecoxib was shown to target CSCs and suppress their self-
renewal, sensitizing them against chemoresistance as well as inhibiting their EMT. Further, these studies