Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling

Valiulienė, Giedrė; Vitkevičienė, Aida; Skliutė, Giedrė; Borutinskaitė, Veronika; Navakauskienė, Rūta

doi:10.3390/molecules26082303

Cited by 12 publications

(9 citation statements)

References 27 publications

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“…It was also suggested that this agent can protect against oxidative stressinduced cell death. 21,22 In the present study, we observed that TOS and OSI values decreased significantly along with metformin treatment, whereas TAS increased, although not significantly.…”

Section: Discussionsupporting

confidence: 44%

Protective effect of metformin on lithium-induced nephrogenic diabetes insipidus: An experimental study in rats

Taş¹,

Sancak²

2021

Adv Clin Exp Med

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Background. Lithium is widely used in the treatment of bipolar disorders and may lead to nephrogenic diabetes insipidus (NDI), following long-term treatment. Metformin is considered the preferred initial therapy for patients with type 2 diabetes mellitus (T2D). Objectives.To investigate the protective effect of metformin on the kidney damage caused by lithium administration. Materials and methods.Using an animal model of chronic lithium-induced NDI, rats were divided into 4 groups: sham, metformin, lithium, and lithium + metformin. The effects of these treatments were examined using serum electrolytes, blood and tissue total antioxidant status, total oxidant status, the oxidative stress index, urine and blood osmolality, and tissue aquaporin-2 (AQP2) levels. Additionally, histopathological changes, including congestion, hydropic swelling, tubular necrosis, tubular atrophy, and Bowman's capsule dilatation, were evaluated. The total histopathological score was obtained by summing the scores for each pathological finding.Results. In the lithium group, biochemical variables indicating NDI, including sodium, chloride and blood osmolality, increased, and urine osmolality decreased, compared to the sham group. With metformin treatment, the blood osmolality decreased from 328. 17 mOsm/kg to 306.33 mOsm/kg, and urine osmolality increased from 349.67 mOsm/kg to 754.50 mOsm/kg (p = 0.004 and p = 0.001, respectively). Tissue AQP2 levels decreased with lithium administration but stabilized with metformin treatment. Additionally, in comparison to the lithium group, the total histopathological score in the metformin group declined from 8.0 to 2.0 (p = 0.002).Conclusions. Metformin may help protect the kidneys from lithium-induced NDI through the AQP2 regulating effect and a reduction in oxidative stress.

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Section: Discussionsupporting

confidence: 44%

Protective effect of metformin on lithium-induced nephrogenic diabetes insipidus: An experimental study in rats

Taş¹,

Sancak²

2021

Adv Clin Exp Med

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“…Loss of MMP in response to S63845 was also reported in DLBCL and AML cells [ 35 , 38 ]. To date, ROS have not been investigated in most lymphoma studies, but their induction was also found in two AML cell lines at 24 h in response to S63845 [ 39 ]. Thus, as resistant CTCL cell lines were completely lacking caspase activation as well as loss of MMP and ROS production in response to S63845, the causes of their resistance had to be sought more above in the pathway.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression

Sumarni

Zhu

Sinnberg

et al. 2022

IJMS

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Long-term, curative treatment of cutaneous T-cell lymphomas (CTCL) remains a major challenge. Therapy resistance is often based on apoptosis deficiency, and may depend on antiapoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Bcl-w and Mcl-1. For their targeting, several antagonists have been generated, which mimic the Bcl-2 homology domain 3 (BH3 mimetics). As dysregulation and overexpression of Mcl-1 has been reported in CTCL, the use of Mcl-1 inhibitors appears as an attractive strategy. Here, we investigated the effects of the selective Mcl-1 inhibitor S63845 in a series of four CTCL cell lines, in comparison to ABT-263 and ABT-737 (inhibitors of Bcl-2, Bcl-xL and Bcl-w). In two cell lines (HH, HuT-78), S63845 resulted in significant apoptosis induction, decrease in cell viability, loss of mitochondrial membrane potential and caspase activation, while two other cell lines (MyLa, SeAx) remained completely resistant. An inverse correlation was found, as S63845-resistant cells were highly sensitive to ABT-263/-737, and S63845-sensitive cells showed only moderate sensitivity to ABTs. Combinations of S63845 and ABT-263 partially yielded synergistic effects. As concerning Bcl-2 protein expression, weaker Mcl-1 expression was found in S63845-resistant MyLa and SeAx, while for Bcl-2 and Bcl-xL, the lowest expression was found in the highly sensitive cell line HH. The most striking difference between S63845-resistant and -sensitive cells was identified for Bcl-w, which was exclusively expressed in S63845-resistant cells. Thus, CTCL may be efficiently targeted by BH3 mimetics, providing the right target is preselected, and Bcl-w expression may serve as a suitable marker.

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“…Additionally, substantial evidence indicated that the remodeling redox status of metformin is relevant to different types of cancer. The apoptosis of acute myeloid leukemia (AML) cells is observed after treatment with metformin, which is mediated by reducing ROS via downregulation of oxidative phosphorylation (OXPHOS) [100]. The proliferation of pancreatic cells and osteosarcoma is also inhibited by metformin-mediated ROS downregulation [101,102].…”

Section: Metformin Exerts Its Effect In An Ampk-independent Manner Me...mentioning

confidence: 99%

Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study

Zhu

Zhou

et al. 2022

Mol Biomed

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Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20–30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.

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Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling

Cited by 12 publications

References 27 publications

Protective effect of metformin on lithium-induced nephrogenic diabetes insipidus: An experimental study in rats

Protective effect of metformin on lithium-induced nephrogenic diabetes insipidus: An experimental study in rats

Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression

Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study

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