Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors

Abo-Elmatty, Dina M.; Ahmed, Eman; Tawfik, Mona K.; Helmy, Seham A.

doi:10.1016/j.intimp.2017.01.002

Cited by 20 publications

(14 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, it was shown to delay the onset of age-related diseases, such as cancer, metabolic syndrome [145], and cognitive disorders [146]. Its mechanism of action is associated with the activation of 5 AMP-activated protein kinase (AMPK) [147,148], inhibition of the mammalian target of rapamycin (mTOR) [149], reduction of DNA damage [150,151], and decreased insulin levels and IGF-1 signaling [152][153][154]. The longevity effect of metformin has not yet been identified in humans, and therefore, its mechanism of action requires further investigation.…”

Section: Metforminmentioning

confidence: 99%

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

et al. 2020

View full text Add to dashboard Cite

Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.

show abstract

Section: Metforminmentioning

confidence: 99%

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In fact, breast cancers from metformin-treated patients exhibit reduced PD-L1 levels, which enhances cytotoxic cell immunity against cancer cells (147). In addition, metformin, lowering the plasma levels of insulin and insulin-like growth factors, might indirectly inhibit the PI3K/Akt/mTOR pathway (148). AMPK activation following metformin treatment has been described in several human cancer cell types including breast (149, 150), endometrial (151), ovarian (152), pancreatic (153, 154), lung (155), prostate (123), head and neck (156), and colon carcinomas (157), often correlating with antiproliferative effects.…”

Section: Development Of Pharmacological Tools To Target Clic1 Activitmentioning

confidence: 99%

Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity

et al. 2019

View full text Add to dashboard Cite

The lack of in-depth knowledge about the molecular determinants of glioblastoma (GBM) occurrence and progression, combined with few effective and BBB crossing-targeted compounds represents a major challenge for the discovery of novel and efficacious drugs for GBM. Among relevant molecular factors controlling the aggressive behavior of GBM, chloride intracellular channel 1 (CLIC1) represents an emerging prognostic and predictive biomarker, as well as a promising therapeutic target. CLIC1 is a metamorphic protein, co-existing as both soluble cytoplasmic and membrane-associated conformers, with the latter acting as chloride selective ion channel. CLIC1 is involved in several physiological cell functions and its abnormal expression triggers tumor development, favoring tumor cell proliferation, invasion, and metastasis. CLIC1 overexpression is associated with aggressive features of various human solid tumors, including GBM, in which its expression level is correlated with poor prognosis. Moreover, increasing evidence shows that modification of microglia ion channel activity, and CLIC1 in particular, contributes to the development of different neuropathological states and brain tumors. Intriguingly, CLIC1 is constitutively active within cancer stem cells (CSCs), while it seems less relevant for the survival of non-CSC GBM subpopulations and for normal cells. CSCs represent GBM development and progression driving force, being endowed with stem cell-like properties (self-renewal and differentiation), ability to survive therapies, to expand and differentiate, causing tumor recurrence. Downregulation of CLIC1 results in drastic inhibition of GBM CSC proliferation in vitro and in vivo, making the control of the activity this of channel a possible innovative pharmacological target. Recently, drugs belonging to the biguanide class (including metformin) were reported to selectively inhibit CLIC1 activity in CSCs, impairing their viability and invasiveness, but sparing normal stem cells, thus representing potential novel antitumor drugs with a safe toxicological profile. On these premises, we review the most recent insights into the biological role of CLIC1 as a potential selective pharmacological target in GBM. Moreover, we examine old and new drugs able to functionally target CLIC1 activity, discussing the challenges and potential development of CLIC1-targeted therapies.

show abstract

“… 49 , 50 Some studies have shown that Met inhibits IGF-1R signaling in cancer cells. 51 – 53 In addition, our group has reported that Met could restore crizotinib sensitivity in crizotinib-resistant NSCLC cells through inhibition of the IGF-1R signaling pathway. 54 To further explore the mechanism involved in the cytotoxicity effect of Met, we investigated the IGF-1R signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway

Pan¹,

Jiao²,

Lin³

et al. 2018

BTT

View full text Add to dashboard Cite

AimAlthough EGFR tyrosine kinase inhibitors (TKIs) have shown dramatic effects against sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), ~20%–30% of NSCLC patients with EGFR-sensitive mutation exhibit intrinsic resistance to EGFR-TKIs. The purpose of the current study was to investigate the enhanced antitumor effect of metformin (Met), a biguanide drug, in combination with gefitinib (Gef) in primary resistant human lung cancer cells and the associated molecular mechanism.Experimental designH1975 cell line was treated with Met and/or Gef to examine the inhibition of cell growth and potential mechanism of action by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki67 incorporation assay, flow cytometry analysis, small interfering RNA technology, Western blot analysis and xenograft implantation.ResultsInsulin-like growth factor-1 receptor (IGF-1R) signaling pathway was markedly activated in EGFR-TKI primary resistant H1975 cells as compared to EGFR-TKI acquired resistance cells (PC-9GR, H1650-M3) and EGFR-TKI sensitivity cells (PC-9, HCC827). Inhibition of IGF-1R activity by AG-1024 (a small molecule of IGF-1R inhibitor), as well as downregulation of IGF-1R by siRNA, significantly enhanced the ability of Gef to suppress proliferation and induce apoptosis in H1975 cells via the inhibition of AKT activation and subsequent upregulation of Bcl-2-interacting mediator of cell death (BIM). Interestingly, the observation showed that Met combined with Gef treatment had similar tumor growth suppression effects in comparison with the addition of AG-1024 to therapy with Gef. A clear synergistic antiproliferative interaction between Met and Gef was observed with a combination index (CI) value of 0.65. Notably, IGF-1R silencing mediated by RNA interference (RNAi) attenuated anticancer effects of Met without obviously resensitizing H1975 cells to Gef. Finally, Met-based combinatorial therapy effectively blocked tumor growth in the xenograft with TKI primary resistant lung cancer cells.ConclusionOur findings demonstrated that Met combined with Gef would be a promising strategy to overcome EGFR-TKI primary resistance via suppressing IGF-1R signaling pathway in NSCLC.

show abstract

Metformin enhancing the antitumor efficacy of carboplatin against Ehrlich solid carcinoma grown in diabetic mice: Effect on IGF-1 and tumoral expression of IGF-1 receptors

Cited by 20 publications

References 55 publications

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity

Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway

Contact Info

Product

Resources

About