# Therapeutic Potential and Challenges of Pioglitazone in Cancer Treatment
## 3 Therapeutic Use of Pioglitazone
### Therapeutic Effect on Different Types of Cancer
#### 3.6.2 Lung Cancer  
According to clinical evidence, PPAR-\(\gamma\) agonists play a major role lung cancer progression. In fact, PPAR-\(\gamma\) agonists have been associated with differentiation, tumor size, BCL2/BAX ratio and c-MYC expression levels, in cases of non-small cell lung cancer (NSCLC), lung adenocarcinoma, and squamous cell lung cancer (SCLC) [70]. Pioglitazone has demonstrated the ability to reduce NSCLC proliferation and invasiveness through downregulation and altering pathways of major significance in proliferation, apoptosis, angiogenesis, and metastatic potential. Indeed, rodent studies have shown that pioglitazone has the potential to reduce tumor formation and volume [71]. Additionally, inflammation is also affected, as pioglitazone inhibits prostaglandin 2 (PGE2) production while bypassing cyclooxygenase 2 (COX-2) [59]. As a chemopre medication, pioglitazone has proven to have little value considering the double-blind clinical trial conducted by [PERSON] et al. (2019), which reported that no significant alterations in the endpoints were noted other than some minor effect on lesions [72]. Chemoprereutive studies were also carried out by [PERSON] et al. (2017), who noted significant reduction in adenoma formation but no noteworthy alteration to the effect of metformin when combined with it, and by a team of similar composure, who evaluated the effectiveness of pioglitazone in an aerosol form [73]. They concluded from animal tests that a dose of 150-450 ug/kg was tolerable, with limited to no adverse effects, and effective, given the reduction in adenoma formation after biochemical and histological assessments [74]. As with BC, pioglitazone has also been considered for combination therapy along with more established anticarcinogenic agents, as studied in the following cases:  
* The use with EGFR Tyrosine Kinase Inhibitors such as gefitinib for NSCLC, as it was found that PPAR-\(\gamma\) mediated upregulation of phosphate, and tensin homolog (PTEN) downregulated the PI3K/Akt pathway that is correlated to resistance to said TKIs [70].
* Combination of pioglitazone with clarithromycin and a relatively small dose of chemotherapeutic agent was compared against nivolumab in the ModuLung trial by [PERSON] et al. (2021) [75]. This trial was terminated early due to the approval of checkpoint inhibitors as first line treatment, with the conclusion that nivolumab was superior to this combination therapy; however, with a difference in the overall survival rate and quality of life between the two regimens being similar, the latter seems to be a viable alternative to be assessed in future trials and be considered in cases with few other options [75].  
Granted that inactivation of PPAR-\(\gamma\) combined with increased presence of prostaglandandins is a dangerous sign, as it leads to loss of control over Ras/Raf/Mek activation and NF-K\(\beta\) mediated proliferation, [PERSON] et al. (2022) tested pioglitazone along with COX-2 specific antagonist celecoxib on rodents. The results were coherent with the hypothesis as decreases in tumor size, alterations to tumor architecture, and increase in lifespan, as well as improvement of its quality, were noted [76].  
However, PPAR-\(\gamma\) also possesses tumor promoting effects regarding lung cancer [77], such as the case of increased tumor progression in orthotropic mice after systemic PPAR-\(\gamma\) activation in the cancer cells as well as the tumor microenvironment [59], and, as such,additional studies regarding the exact effects of pioglitazone in a clinical setting and risk-benefit assessment in the given context are needed.