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Towards Chemoresistance Reduction in Laryngeal Cancer: Development of a Chemoresistant Laryngeal Cell Culture Model for Evaluating Chemosensitizing Strategies /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Towards Chemoresistance Reduction in Laryngeal Cancer: Development of a Chemoresistant Laryngeal Cell Culture Model for Evaluating Chemosensitizing Strategies // Christian Rafael Moya Garcia.
Author:	Garcia, Christian Rafael Moya,
Description:	1 electronic resource (241 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-08, Section: B.
Contained By:	Dissertations Abstracts International86-08B.
Subject:	Cellular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31836578
ISBN:	9798304946230

Towards Chemoresistance Reduction in Laryngeal Cancer: Development of a Chemoresistant Laryngeal Cell Culture Model for Evaluating Chemosensitizing Strategies /
Garcia, Christian Rafael Moya,

Towards Chemoresistance Reduction in Laryngeal Cancer: Development of a Chemoresistant Laryngeal Cell Culture Model for Evaluating Chemosensitizing Strategies /Christian Rafael Moya Garcia. - 1 electronic resource (241 pages)

Source: Dissertations Abstracts International, Volume: 86-08, Section: B.

The goal of this thesis project was to reduce the chemoresistance of laryngeal cancer cells to docetaxel drugs with an adjuvant treatment of metformin. Laryngeal squamous cell carcinoma (LSCC) is a subtype of head and neck cancer that critically affects daily activities of speaking, swallowing, and breathing. LSCC accounts for over 30% of all head and neck cancer cases globally on an annual basis, ranking second in prevalence after oral cancer. First-line chemotherapy for LSCC includes docetaxel, cisplatin, and 5-fluorouracil. Yet, chemoresistance remains a major challenge for patients with LSCC not associated with human papilloma virus infection, with about 50% of a 5-year overall survival rate. Systemic delivery of chemotherapeutics, either via a vein or an artery, is prone to induce deleterious side effects including high toxicities and locoregional extravasation. De-escalation strategies like the use of chemosensitizers were proposed to reduce long-term toxicities while increasing drug bioavailability at the tumor site. Metformin, an antiglycemic agent, was shown to inhibit cancer cells' metabolic activity via the mammalian target of rapamycin; thus, enhances chemotherapy effects on tumor reduction.First, we proposed to load docetaxel into lipid nanocarriers to shield docetaxel, a lipophilic drug, from early degradation that led to increased drug availability. A chitosan mucoadhesive coating on lipid nanocarriers was used to enhance drug retention within tumors. Such a coating was crucial because interstitial fluids can rapidly wash away drugs. The mucoadhesive coating helped retain docetaxel within the tumor, facilitating localized treatment. Study results confirmed that chitosancoated lipid nanocarriers, i.e., chitosomes, were successfully taken up into the cytoplasm of human LSCC, demonstrating effective docetaxel delivery by the nanocarriers. Docetaxel-loaded chitosomes exhibited significantly higher cytotoxicity in LSCC when compared to stromal laryngeal fibroblasts (30% vs. 10%; p < 0.05). No hemolytic effects were observed on human red blood cells and thus support potential intra-arterial delivery of these chitosan-based nanocarriers.Next, considering the resistant nature of laryngeal cancer, we developed a docetaxel-resistant LSCC model by using an in-house docetaxel escalating exposure protocol for 4 months. Cells were compared with known chemoresistance genotypes and phenotypes via transcriptomic and functional analyses. Compared to control groups, chemoresistant-specific pathways of PI3K/mTOR and autophagy were upregulated in docetaxel-exposed LSCC, which matched the literature of chemoresistance development in aggressive tumors. Functional cytotoxic experiments were further performed by subjecting the cells to docetaxel treatments. Results confirmed that the cells showed 36% more viability compared to the LSCC, indicating these cells acquired chemoresistance and were less responsive to the drug.Finally, we evaluated the effect of combined metformin and docetaxel therapy in a microfluidic system. We developed a 2-channel laryngeal-tumor-on-a-chip model by co-culturing docetaxel-resistant LSCC and stromal laryngeal fibroblasts. With the dynamic perfusion, hypoxic gradient was created within the chips as in vivo laryngeal tumor core. The migration of stromal laryngeal fibroblasts into chemoresistant LSCC was observed toward the hypoxic gradient. Moreover, the proposed chip cultures were exposed to metformin and docetaxel-loaded chitosomes. Increased cell death was observed in stromal fibroblasts and cancer cells, compared to drug alone controls (55% vs. 15%; p < 0.05) 5 days after the treatment. Chitosome uptake was noticed after 6-hr inspection in both cell groups. This thesis presented a reliable and representative in vitro model of chemoresistant laryngeal cancers that will contribute to developing new therapeutic strategies for reducing drug resistance and tumor recurrence.

English

ISBN: 9798304946230Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Laryngeal cancer cells

Towards Chemoresistance Reduction in Laryngeal Cancer: Development of a Chemoresistant Laryngeal Cell Culture Model for Evaluating Chemosensitizing Strategies /
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520 $a The goal of this thesis project was to reduce the chemoresistance of laryngeal cancer cells to docetaxel drugs with an adjuvant treatment of metformin. Laryngeal squamous cell carcinoma (LSCC) is a subtype of head and neck cancer that critically affects daily activities of speaking, swallowing, and breathing. LSCC accounts for over 30% of all head and neck cancer cases globally on an annual basis, ranking second in prevalence after oral cancer. First-line chemotherapy for LSCC includes docetaxel, cisplatin, and 5-fluorouracil. Yet, chemoresistance remains a major challenge for patients with LSCC not associated with human papilloma virus infection, with about 50% of a 5-year overall survival rate. Systemic delivery of chemotherapeutics, either via a vein or an artery, is prone to induce deleterious side effects including high toxicities and locoregional extravasation. De-escalation strategies like the use of chemosensitizers were proposed to reduce long-term toxicities while increasing drug bioavailability at the tumor site. Metformin, an antiglycemic agent, was shown to inhibit cancer cells' metabolic activity via the mammalian target of rapamycin; thus, enhances chemotherapy effects on tumor reduction.First, we proposed to load docetaxel into lipid nanocarriers to shield docetaxel, a lipophilic drug, from early degradation that led to increased drug availability. A chitosan mucoadhesive coating on lipid nanocarriers was used to enhance drug retention within tumors. Such a coating was crucial because interstitial fluids can rapidly wash away drugs. The mucoadhesive coating helped retain docetaxel within the tumor, facilitating localized treatment. Study results confirmed that chitosancoated lipid nanocarriers, i.e., chitosomes, were successfully taken up into the cytoplasm of human LSCC, demonstrating effective docetaxel delivery by the nanocarriers. Docetaxel-loaded chitosomes exhibited significantly higher cytotoxicity in LSCC when compared to stromal laryngeal fibroblasts (30% vs. 10%; p < 0.05). No hemolytic effects were observed on human red blood cells and thus support potential intra-arterial delivery of these chitosan-based nanocarriers.Next, considering the resistant nature of laryngeal cancer, we developed a docetaxel-resistant LSCC model by using an in-house docetaxel escalating exposure protocol for 4 months. Cells were compared with known chemoresistance genotypes and phenotypes via transcriptomic and functional analyses. Compared to control groups, chemoresistant-specific pathways of PI3K/mTOR and autophagy were upregulated in docetaxel-exposed LSCC, which matched the literature of chemoresistance development in aggressive tumors. Functional cytotoxic experiments were further performed by subjecting the cells to docetaxel treatments. Results confirmed that the cells showed 36% more viability compared to the LSCC, indicating these cells acquired chemoresistance and were less responsive to the drug.Finally, we evaluated the effect of combined metformin and docetaxel therapy in a microfluidic system. We developed a 2-channel laryngeal-tumor-on-a-chip model by co-culturing docetaxel-resistant LSCC and stromal laryngeal fibroblasts. With the dynamic perfusion, hypoxic gradient was created within the chips as in vivo laryngeal tumor core. The migration of stromal laryngeal fibroblasts into chemoresistant LSCC was observed toward the hypoxic gradient. Moreover, the proposed chip cultures were exposed to metformin and docetaxel-loaded chitosomes. Increased cell death was observed in stromal fibroblasts and cancer cells, compared to drug alone controls (55% vs. 15%; p < 0.05) 5 days after the treatment. Chitosome uptake was noticed after 6-hr inspection in both cell groups. This thesis presented a reliable and representative in vitro model of chemoresistant laryngeal cancers that will contribute to developing new therapeutic strategies for reducing drug resistance and tumor recurrence.
520 $a L'objectif de cette these a ete de reduire la chimioresistance des cellules cancereuses du larynx auxmedicaments a base de docetaxel et la metformine. Le carcinome epidermoide du larynx (CELC)est un sous-type du cancer de la tete et du cou qui affecte gravement les activites quotidiennes tellesque parler, avaler et respirer. Le CELC represente plus de 30% de tous les cas de cancer de la teteet du cou dans le monde par an La chimiotherapie pour le CELC comprend le docetaxel, lecisplatine et le 5-fluorouracile. Cependant, la chimioresistance demeure un defi majeur pour lespatients atteints de CELC non associe a une infection par le virus du papillome humain, avec 50%de taux de survie globale a cinq ans. L'administration systemique de la chimiotherapie, par voieveineuse ou arterielle, est susceptible d'entrainer des effets secondaires, notamment des toxiciteselevees et une extravasation locoregionale. L'utilisation de chimiosensibilisants a ete proposeepour reduire les toxicites a long terme tout en augmentant la biodisponibilite des medicaments dansla tumeur. La metformine a ete demontree pour inhiber l'activite metabolique des cellulescancereuses liee a la mTOR, ameliorant ainsi l'efficacite de la chimiotherapie dans les tumeurs.Nous avons propose de charger le docetaxel dans des nanovecteurs lipidiques pour le proteger dela degradation precoce. Un revetement mucoadhesif en chitosane sur les nanovecteurs a ete utilisepour ameliorer la retention du docetaxel dans les tumeurs. Le revetement mucoadhesif a aide amaintenir le docetaxel dans la tumeur, facilitant le traitement localise. Les resultats de l'etude ontconfirme que les nanovecteurs lipidiques enrobes de chitosane, c'est-a-dire les «chitosomes»,etaient efficacement pris dans le cytoplasme du CELC humain. Les chitosomes charges dedocetaxel ont montre une cytotoxicite plus elevee dans le CELC par rapport aux fibroblastes dularynx (30% vs. 10%; p < 0.05). Aucun effet hemolytique n'a ete observe sur les globules rougeshumains, soutenant ainsi une eventuelle administration intra-arterielle de ces chitosomes.Ensuite, nous avons genere un CELC resistant au docetaxel en utilisant un protocole d'expositionprogressive au docetaxel pendant 4 mois. Les cellules ont ete comparees a des phenotypes dechimioresistance connus par les analyses transcriptomiques et fonctionnelles. Par rapport auxgroupes temoins, les voies specifiques de la chimioresistance du PI3K/mTOR et de l'autophagieont ete surexprimees dans le CELC expose au docetaxel. Des experimentations cytotoxiques ontensuite ete realisees en soumettant les cellules a des traitements au docetaxel. Les resultats ontconfirme que les cellules avaient acquis une chimioresistance et etaient 15% moins sensibles aumedicament.Enfin, nous avons evalue l'effet de la therapie combinee de metformine et de docetaxel avec dessystemes microfluidiques. Nous avons developpe des modeles de cancer du larynx sur puce a 2canaux en co-cultivant des CELC resistants au docetaxel et des fibroblastes du larynx. Grace a laperfusion dynamique, un gradient hypoxique a ete cree dans les puces simulant le noyau tumorallarynge in vivo. La migration des fibroblastes vers les CELC resistants a ete observee en directiondu gradient hypoxique. De plus, une perfusion de 12 minutes de chitosomes charges de docetaxela ete realisee pour imiter l'administration intra-arterielle comme en pratique clinique. Uneaugmentation de la mort cellulaire des fibroblastes et CELC resistants ont ete observe apres lesinjections combines de metformine et de chitosomes par rapport aux temoins medicamenteux seuls(55% contre 15% ; p < 0,05) 5 jours apres le traitment.
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650 4 $a Cellular biology. $3 3172791
650 4 $a Oncology. $3 751006
650 4 $a Health sciences. $3 3168359
653 $a Laryngeal cancer cells
653 $a Rapamycin
653 $a Drug availability
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710 2 $a McGill University (Canada). $e degree granting institution. $3 3759190
720 1 $a Li-Jessen, Nicole $e degree supervisor.
720 1 $a Tabrizian, Maryam $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-08B.
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791 $a Ph.D.
792 $a 2024
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