Add like
Add dislike
Add to saved papers

Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1α.

Molecular Oncology 2023 August 17
Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex-I inhibitors. The treatment downregulated genes mediating hypoxia-inducible factor (HIF)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1α (HIF-1α) signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

Full text links

We have located links that may give you full text access.
Can't access the paper?
Try logging in through your university/institutional subscription. For a smoother one-click institutional access experience, please use our mobile app.

For the best experience, use the Read mobile app

Group 7SearchHeart failure treatmentPapersTopicsCollectionsEffects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure Importance: Only 1 class of glucose-lowering agents-sodium-glucose cotransporter 2 (SGLT2) inhibitors-has been reported to decrease the risk of cardiovascular events primarily by reducingSeptember 1, 2017: JAMA CardiologyAssociations of albuminuria in patients with chronic heart failure: findings in the ALiskiren Observation of heart Failure Treatment study.CONCLUSIONS: Increased UACR is common in patients with heart failure, including non-diabetics. Urinary albumin creatininineJul, 2011: European Journal of Heart FailureRandomized Controlled TrialEffects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.Review

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app

Read by QxMD is copyright © 2021 QxMD Software Inc. All rights reserved. By using this service, you agree to our terms of use and privacy policy.

You can now claim free CME credits for this literature searchClaim now

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app