Letter to Editor

Inhibition of COX-2 and PI3K/AKT Pathways to Prevent Cancer Metastasis

To the Editor,

Metastasis of cancer is one of the main reasons for treatment failure and poorer prognosis of patients with metastatic cancers such as non-small cell lung cancer (NSCLC).¹ Metastasis is central to these pathways, as complex interactions between tumor cells and the host microenvironment are necessary for metastatic spread. Tumor progression, inflammation-driven has been confirmed for a decade, and targeting these pathways in cancer patients has been actively studied as cancer therapy.^2,3 Cyclooxygenase-2 (COX-2), the principal isoform over-expressed in many cancers, including NSCLC, can exert a pro-inflammatory effect and support tumor growth/migratory capacities by further promoting angiogenesis. COX-2-derived prostaglandins contribute to cancer cell survival, invasiveness, and resistance to apoptosis. Additionally, COX-2 activation triggers downstream signaling pathways, such as PI3K/AKT, which play a crucial role in metastasis and tumor cell survival. COX-2 overexpression in tumor cells also leads to subsequent downstream signaling such as activation of the PI3K/AKT downstream pathway, an essential factor for metastasis and resistance to apoptosis.⁴ Recent studies demonstrate the COX-2 inhibitor, celecoxib, may be one tool for halting tumor progression and metastasis. Inhibitors are effective in the clinic to prevent the metastatic spread and lower the side effects of currently used chemo.⁵ COX-2 inhibitors can target inflammatory aspects but the antimetastatic impact is under-determined, and thus further investigation of therapeutic interventions is necessary as an improvement.⁶ NS398, a COX-2 inhibitor in itself and similarly in combination with either of 2 PI3K/AKT inhibitors LY294002 has been detected to implement a G2/M arrest in WM35 melanoma cells signifying their potential in cancer treatment.⁷ PI3K-AKT inhibitors have also been reported to function as an effectual suppressor of COX-2 inhibitors further lowering cell proliferation and migration in lung cancer cells, synergistically. This may indicate that targeting both pathways represents a more potent therapeutic strategy against metastasis.⁸

An efficient and unique way might be the design of dual-target inhibitors, that can inhibit two inflammatory pathways in tandem, one targeting COX-2 and the other one the PI3K/AKT pathway. The PI3K/AKT axis is well-known to be essential for the regulation of cell survival, growth, and migration. Its activation when induced by COX-2 signaling significantly contributes to cancer metastasis.⁹ Due to targeting both COX-2 and PI3K/AKT pathways, these dual-target inhibitors, consequently fall on many of other pro-tumorigenic & metastatic processes causing a more holistic strategy to combat cancer metastasis.¹⁰ Although with considerable potential, no dual-target inhibitors have been developed and translated into clinical practice thus far. The most significant obstacle pertinent to its development is the need to target selectivity and reduce off-target effects.¹¹ It requires an in-depth investigation of the pharmacokinetics and safety of these inhibitors to prove efficacy without being patient-unsafe formulations.¹² Preclinical and clinical work must target to overcome these challenges by further enhancing drug formulations as well as identifying the most appropriate subset of patients for these therapies.¹³ Combining COX-2 inhibitors with PI3K/AKT inhibitors, or developing next-generation dual-target agents, presents a promising strategy for therapeutic advancement. With this approach, it can fortify current cancer therapy, decrease metastasis potential, and provide patients with a superior way to stabilize disease progression.¹⁴ Further studies are needed to assess the clinical utility of dual-target inhibitors in conjunction with standard-of-care therapy and confirm the validity of how they can be translated to clinical applications.

Finally, double targeting of COX-2 and PI3K/AKT pathways in inhibition of inflammation-dependent cancer progression may pave new avenues for metastasis reduction on top of clinical benefit in cancer patients. Research focused on dual-target inhibitors could substantially increase the efficacy of cancer therapies and would be an exciting approach to overcoming the challenges underlying metastatic disease.¹⁵ Continued studies of dual-target inhibitors, possibly supported by approaches to surmount challenges in their translational implementation might lead to major benefits for cancer therapies, and therefore provide a hopeful roadmap for addressing the challenges of metastasis.

We encourage further investigation in this area to realize the full therapeutic potential of these promising combination strategies.

Competing Interests

The authors state that there is no competing/conflict of interest.

Ethical Approval

Not applicable.

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