# Therapeutic Potential and Challenges of Pioglitazone in Cancer Treatment
## 3 Therapeutic Use of Pioglitazone
### Therapeutic Effect on Different Types of Cancer  
#### 3.6.1 Breast Cancer  
According to retrospective cohort studies, there is insignificant to almost no elevated breast cancer (BC) risk related to the use of pioglitazone [64]. It is important to note that PPAR-\(\gamma\) levels are reduced and methylation of PPAR-\(\gamma\) promoter is increased in BC cells, leading to the indication of its unfavorable role in cancer proliferation. In the example of triple negative breast cancer (TNBC), pioglitazone has proven its value as an adjuvant in the combined use with doxorubicin, as it decreases the invasiveness and tendency for migration,  
\begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Process** & **Mechanism** & **Cancer Type** \\ \hline Drug sensitization & Reduced expression of metallothioneen and endorphin connected to SZ73 phosphorylation [60]. & Pancreatic cancer \\ \cline{2-3}  & Enhanced type I Interferon activity due to inhibition of the STAT-3 pathway [58]. & Leukemia \\ \cline{2-3}  & Increased arsenic trioxide induced tumor toxicity through inhibition of the PI3K/ AKT pathway [45]. & \\ \cline{2-3}  & Doxorubicin sensitization via modulation of P-glycoprotein [56]. & Osteosarcoma \\ \cline{2-3}  & Reduced resistance to cisplatin [46]. & \\ \hline  & Increased cisplatin and oxaliplatin efficacy. & \\ \cline{2-3}  & Inhibited EGFR/MDM2 mediated chemoresistance and PPAR-\(\gamma\) degradation [50]. & Thyroid, lung, prostate, breast, kidney, esophageal and urothelial cancer \\ \cline{2-3}  & Downregulation of cyclin dependent kinase 4 (CDK4). & \\ \cline{2-3}  & Upregulation of CDK inhibitors including p19, p21, p27 and rho-related GTP binding protein. & \\ \cline{2-3}  & Activation of Rb protein [51,60]. & \\ \cline{2-3}  & Downregulation of cyclins D, cyclin E, CDK2, CDK4, proliferating nuclear antigen and retinoblastoma protein [58]. & Breast and colorectal cancer \\ \cline{2-3}  & Induction of G1-arrest through the activation of p21 along with the upregulation of FOXO3a [61]. & Acute promyelotic leukemia (NB4 cells) \\ \hline Accelerated differentiation & Induced adipogenesis [57]. & Melanoma \\ \hline Immunomodulation & Increased \(\beta\)3 and \(\alpha\)5 integrin expression [57]. & Colorectal cancer \\ \cline{2-3}  & Reduced PD-L1 levels due to autophagy [62]. & Lung, colorectal cancer \\ \hline Bioenergetic disruption & Reduced pyruvate oxidation and glutathione levels. & Hepatocellular carcinoma \\ \cline{2-3}  & ROS-induced stress mediated by HIF-1 and NF-\(\kappa\beta\) signaling. & \\ \hline  & Downregulation of smad family member 3 (SMAD3), PDK1 and MCT-1. & \\ \cline{2-3}  & Upregulation of plasminogen activator inhibitor-1 (PAI-1). & \\ \cline{2-3}  & Downregulation of NF-\(\kappa\beta\), eIF2\(\alpha\), MMP9 and fibronectin [46]. & Lung cancer \\ \cline{2-3}  & Upregulation of CXCR4, CXCR, E-cadherin [47]. & \\ \cline{2-3}  & Downregulation of TGF-\(\beta\). & Glioma \\ \cline{2-3}  & Reduced expression and invasiveness of \(\beta\)-catenin [46]. & Breast cancer \\ \cline{2-3}  & Downregulation of TGF\(\beta\)R1 and SMAD3 associated with epithelial to mesenchymal transition (EMT) [63]. & Non-small cell lung cancer \\ \hline  & Upregulation of HIF-1 and BNIP3 [51]. & Breast and prostate cancer \\ \cline{2-3}  & Activation of PI3K [61]. & Acute promyelotic leukemia (NB4 cells) \\ \hline \hline \end{tabular}
\end{table}
Table 1: _Cont._an issue commonly associated with the use of the latter. Similar findings were also reported for the apoptosis-inducing capabilities of cisplatin during in vitro testing [50; 65]. PPAR-\(\gamma\) facilitates major regulatory processes such as the promotion of CXCR4 and CXCR7 genes, inhibition of eIF2\(\alpha\), and intracellular accumulation of glucose-affecting related migration pathways [66; 67]. Despite the aforementioned evidence, there is no clinical application yet [68; 69].