Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole

Karve, Aniruddha; Desai, Janki; Dave, Nimita; Wise‐Draper, Trisha M.; Gudelsky, Gary A.; Phoenix, Timothy N.; Dasgupta, Biplab; Sengupta, Soma; Plas, David R.; Desai, Pankaj B.

doi:10.1007/s00280-022-04469-5

Cited by 9 publications

(3 citation statements)

References 46 publications

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“…Aromatase catalyzes the final step of estradiol synthesis and has been targeted by aromatase inhibitors for the treatment of estrogen receptor-positive breast cancers [ 65 ]. Our studies have shown that letrozole at non-cytotoxic concentrations causes a marked reduction in the IC 50 values of TMZ against TMZ-sensitive and TMZ-resistant patient-derived GBM cells, through the significant enhancement of DNA damage and apoptosis imparted by TMZ [ 20 ]. Letrozole effectively penetrates the BBB and localizes in the tumoral region in orthotopic GBM tumor-bearing rats, and also has no pharmacokinetic drug–drug interactions with TMZ [ 17 , 66 , 67 ].…”

Section: Approaches For Overcoming Tmz Resistance In Gbmmentioning

confidence: 99%

“…Relative to the plasma drug levels, the TMZ brain partitioning ranged between 10–47%. The concentrations of TMZ needed to induce 50% cytotoxicity (IC 50 ) in drug-sensitive GBM cells are in the range of 1–5 µM [ 19 , 20 ]. However, when the tumor cells develop drug resistance, the IC 50 values often exceed 100 µM [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…The concentrations of TMZ needed to induce 50% cytotoxicity (IC 50 ) in drug-sensitive GBM cells are in the range of 1–5 µM [ 19 , 20 ]. However, when the tumor cells develop drug resistance, the IC 50 values often exceed 100 µM [ 19 , 20 ]. There is little accumulation at the steady state following multiple dosing, given the short elimination half-life of TMZ [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

Karve,

Desai,

Gadgil

et al. 2024

IJMS

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A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.

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Section: Approaches For Overcoming Tmz Resistance In Gbmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

Karve,

Desai,

Gadgil

et al. 2024

IJMS

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Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma

Pun,

Prakash,

Demaree

et al. 2024

Adv Healthcare Materials

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Microphysiological systems (MPSs) reconstitute tissue interfaces and organ functions, presenting a promising alternative to animal models in drug development. However, traditional materials like polydimethylsiloxane (PDMS) often interfere by absorbing hydrophobic molecules, affecting drug testing accuracy. Additive manufacturing, including 3D bioprinting, offers viable solutions. GlioFlow3D, a novel microfluidic platform combining extrusion bioprinting and stereolithography (SLA) is introduced. GlioFlow3D integrates primary human cells and glioblastoma (GBM) lines in hydrogel‐based microchannels mimicking vasculature, within an SLA resin framework using cost‐effective materials. The study introduces a robust protocol to mitigate SLA resin cytotoxicity. Compared to PDMS, GlioFlow3D demonstrated lower small molecule absorption, which is relevant for accurate testing of small molecules like Temozolomide (TMZ). Computational modeling is used to optimize a pumpless setup simulating interstitial fluid flow dynamics in tissues. Co‐culturing GBM with brain endothelial cells in GlioFlow3D showed enhanced CD133 expression and TMZ resistance near vascular interfaces, highlighting spatial drug resistance mechanisms. This PDMS‐free platform promises advanced drug testing, improving preclinical research and personalized therapy by elucidating complex GBM drug resistance mechanisms influenced by the tissue microenvironment.

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Multiple therapeutic approaches of glioblastoma multiforme: From terminal to therapy

Kumari

Gupta

Ambasta

et al. 2023

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Potentiation of temozolomide activity against glioblastoma cells by aromatase inhibitor letrozole

Cited by 9 publications

References 46 publications

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

Rapid Biofabrication of an Advanced Microphysiological System Mimicking Phenotypical Heterogeneity and Drug Resistance in Glioblastoma

Multiple therapeutic approaches of glioblastoma multiforme: From terminal to therapy

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