Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer

Kiran, Ammu V. V. V. Ravi; Kumari, Garikapati Kusuma; Krishnamurthy, Praveen Thaggikuppe

doi:10.1007/s10637-021-01158-7

Cited by 7 publications

(3 citation statements)

References 37 publications

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“…Nevertheless, it may be also possible to potentially restore levels of ACOX2 in patients where decreased ACOX2 is expressed through (PPAR)-α/γ dual activators such as SN158, which was shown to significantly upregulate ACOX2 mRNA [ 89 ], although such drugs have yet to enter the clinic due to serious side effects. Nevertheless, both in vitro and in vivo studies suggest that PPAR based agonists such as pioglitazone may have potential for treating NSCLC [ 90 – 92 ], however some degree of caution is indicated as other studies of such agonists suggest that when activated in myeloid cells of the tumour microenvironment, this may aggravate and promote lung cancer progression [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Altered expression of ACOX2 in non-small cell lung cancer

et al. 2022

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Peroxisomes are organelles that play essential roles in many metabolic processes, but also play roles in innate immunity, signal transduction, aging and cancer. One of the main functions of peroxisomes is the processing of very-long chain fatty acids into metabolites that can be directed to the mitochondria. One key family of enzymes in this process are the peroxisomal acyl-CoA oxidases (ACOX1, ACOX2 and ACOX3), the expression of which has been shown to be dysregulated in some cancers. Very little is however known about the expression of this family of oxidases in non-small cell lung cancer (NSCLC). ACOX2 has however been suggested to be elevated at the mRNA level in over 10% of NSCLC, and in the present study using both standard and bioinformatics approaches we show that expression of ACOX2 is significantly altered in NSCLC. ACOX2 mRNA expression is linked to a number of mutated genes, and associations between ACOX2 expression and tumour mutational burden and immune cell infiltration were explored. Links between ACOX2 expression and candidate therapies for oncogenic driver mutations such as KRAS were also identified. Furthermore, levels of acyl-CoA oxidases and other associated peroxisomal genes were explored to identify further links between the peroxisomal pathway and NSCLC. The results of this biomarker driven study suggest that ACOX2 may have potential clinical utility in the diagnosis, prognosis and stratification of patients into various therapeutically targetable options.

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Section: Discussionmentioning

confidence: 99%

Altered expression of ACOX2 in non-small cell lung cancer

et al. 2022

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“…In addition, the slow release of fluid, peripheral oedema, development of chronic kidney disease, and liver dysfunction promoted by PIO [ 2 , 19 , 20 , 21 ] can be attributed to insufficient production of ATP for ion pumps and exchangers in the plasma membrane. Moreover, the reduction of the mitochondrial Ca 2+ -retention capacity and the cancellation of the suppression of mPTP by adenine nucleotides ( Figure 2 ) can be a reason for the toxicity of PIO in several cell lines [ 23 , 24 , 25 , 26 ]. At the same time, the reduction of the risk of myocardial infarction and stroke in patients with clinical manifestation of cardiovascular disease might be connected with long-term effects of PIO, such as the regulation of autophagy and mitochondrial quality control ( Figure 8 ) [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Liver dysfunctions, including hepatitis, deregulation of the level of hepatic enzymes, and mixed hepatocellular-cholestatic liver injury, as well as liver failure with or without fatal outcomes, have been reported to be associated with the intake of PIO [ 21 ]. Besides, PIO significantly increases the risk of bladder cancer [ 22 ] but can display cytotoxic and cytostatic effects on several cancer cell lines [ 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

et al. 2021

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Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨm was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨm in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca2+. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K+ and Ca2+ inward transport but drastically decreased the mitochondrial Ca2+-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO.

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COX‐2 in lung cancer: Mechanisms, development, and targeted therapies

Liu,

Zhang,

Sun

et al. 2024

Chronic Diseases and Translational Medicine

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Lung cancer (LC) is the leading cause of cancer‐related death worldwide, with non‐small cell lung cancer (NSCLC) comprising 85% of all cases. COX‐2, an enzyme induced significantly under stress conditions, catalyzes the conversion of free arachidonic acid into prostaglandins. It exhibits high expression in various tumors and is closely linked to LC progression. COX‐2 functions as a pivotal driver in cancer pathogenesis by promoting prostaglandin E2 synthesis and facilitating tumor cell occurrence and development. Furthermore, COX‐2 holds potential as a predictive marker for early‐stage NSCLC, guiding targeted therapy in patients with early COX‐2 overexpression. Additionally, combining COX‐2 inhibitors with diverse treatment modalities enhances tumor therapeutic efficacy, minimizes adverse effects on healthy tissues, and improves overall patient survival rates posttreatment. In conclusion, combined therapy targeting COX‐2 presents a promising novel strategy for NSCLC treatment, offering avenues for improving prognosis and effective tumor treatment. This review provides novel insights and ideas for developing new treatment strategies to improve the prognosis of NSCLC.

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Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer

Cited by 7 publications

References 37 publications

Altered expression of ACOX2 in non-small cell lung cancer

Altered expression of ACOX2 in non-small cell lung cancer

Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

COX‐2 in lung cancer: Mechanisms, development, and targeted therapies

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