# Therapeutic Potential and Challenges of Pioglitazone in Cancer Treatment
## 3 Therapeutic Use of Pioglitazone
### Therapeutic Effect on Different Types of Cancer
#### 3.6.8 Hematological Malignancies  
There is a great amount of interest in the potential of piogltazone in blood cancers. Studies conducted by [PERSON] et al. (2021) on U937 cells, modeling acute myeloid leukemia (AML) cancer cells, have shown in their results that piogltazone dampened their survival and development capabilities, led to accumulation of cells in the G1 and pre-G1 cell cycle phases, and induction of apoptosis, as indicated by the increase in the population of cells that test positive for Annexin-V and PI [105]. Similar targeted antiproliferative effects were also observed on HL60 (modeling Acute Pro-myelocytic Leukemia-APL), K562 (modeling Chronic Myeloid Leukemia), and Jurkat (modeling T-cell lymphoma) cells, and the cell cycle of the HL60 line also demonstrated accumulation in the G1 phase and decrease in the G2 and metaphasis populations [106]. Jurkat cells were also assessed with the combination of piogltazone and valpro acid, with optimistic results as cell cycle deregulation was noted [107; 108; 109]. According to in vitro studies in different types of leukemia--AML in U937 cells, APL in Jurkat cells, ALL in SD-1, IM-9, Sup-B15, and NALM-6 cells--the primary mode of action for piogltazone is cell cycle arrest [110]. Adding to the above are the tests on Philadelphia chromosome positive leukemic cells by [PERSON] et al. (2017), which reported the antineoplastic effects of piogltazone on cells bearing the T315I mutation while sparing normal CD34 expressing cells and inducing the phosphorylation of the AMP-activated protein kinase (AMPK) [111]. The combination of piogltazone with PI3K inhibitors can potentiate its cytotoxic effects, as was observed on NB4 cells (APL) when they were treated with piogltazone, and PI3K inhibitors CAL-101 and BKM120. The suggested mechanism of synergy is the cell cycle arrest, as analyzed before, mediated by p21 [112]. However, in NALM-6 cell line experiments, where similar synergy was noted, it was found that said effects are interfered with by NF-\(\upbeta\) signaling and autophagy [113]. Potential synergy was also noticed in more conventional chemotherapeutics with a statistically insignificant remission rate being reported for cytarabine and daunorubicin in the clinical study conducted by [PERSON] et al. (2019) [114]. Additionally, as noted in Table 1, piogltazone is correlated with elevated effectiveness of arsenic trioxide [115]. Adjuvant use of piogltazone has been proven to positively influence interventions utilizing BCR-ABL1 tyrosine kinase inhibitors (TKIs) in Chronic Myeloid Leukemia (CML). In vitro experiments carried out on K562 cells by [PERSON] et al. (2016) resulted in the eradication of leukemia stem cells (LSCs), progenitors, and differentiated CML cells [116; 117]. A small phase II clinical trial by [PERSON] et al. (2016) involving 24 subjects treated with imatinib, who were administered piogltazone at a dosage ranging from 30 mg/d to 45 mg/d, exhibited that about half of the patients showed response within one year, with no significant adverse effects other than edema, higher than the rate of 23% in monotherapy with imatinib, thus suggesting correlation between the synergy of piogltazone and favorable outcomes [118]. Additional discontinuation trials such as EDI-PIO in Brazil have raised the issue of alterations in the lipid metabolism and metabolomic profile of the patients, given the effects of piogltazone on the adipose tissue, and the aspect of mitochondrial dysfunction that influences the proliferation of CML cells [106]. However, results originating from the same study, suggest that piogltazone does not affect STAT5 expression and, therefore, the levels of downstream molecules to it, such as HIF-2\(\upalpha\), contrary to the statements of previous reports [119].