Adaptive response of resistant cancer cells to chemotherapy

Chern, Yi‐Jye; Tai, Isabella T.

doi:10.20892/j.issn.2095-3941.2020.0005

Cited by 33 publications

(20 citation statements)

References 256 publications

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“…Consistent with our previous observation of low cytotoxic and cytostatic potential of 4’-FlU (23), these results indicate that mitigated immunopathogenesis in treated animals is a consequence of reduced virus load rather than a direct immunomodulatory effect of the compound. Although essentially sterilizing, even prophylactic treatment resulted in partial protection of animals at re-infection despite the absence of neutralizing antibodies, indicating that treated animals also mounted a viable cell-mediated adaptive response (47, 48).…”

Section: Discussionmentioning

confidence: 99%

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

Lieber

Aggarwal

Yoon

et al. 2022

Preprint

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Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4-Fluorouridine (4-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus, we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium organoids, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar potency in organoids. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented direct-contact transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1) (Ca09) with 2 mg/kg 4-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating an unusually broad window for effective intervention. Therapeutic oral 4-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pandemic Ca09. Recoverees were fully protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4-FlU and supports 4-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

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Section: Discussionmentioning

confidence: 99%

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

Lieber

Aggarwal

Yoon

et al. 2022

Preprint

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“…These results indicated that the ECM1 expression level is tightly related to CRC resistance to 5-FU. Drug resistance is one major cause of chemotherapy failure and cancer mortality (Chern and Tai, 2020;Sun et al, 2020), and verifying the underlying molecular mechanism is urgently needed. Drug resistance is often accompanied by increased cellular growth pathways and enhanced metastatic potential (Dongre and Weinberg, 2019).…”

Section: Discussionmentioning

confidence: 99%

ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction

et al. 2022

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5-Fluorouracil (5-FU) chemoresistance is a persistent impediment to the efficient treatment of many types of cancer, yet the molecular mechanisms underlying such resistance remain incompletely understood. Here we found CRC patients resistant to 5-FU treatment exhibited increased extracellular matrix protein 1 (ECM1) expression compared to CRC patients sensitive to this chemotherapeutic agent, and higher levels of ECM1 expression were correlated significantly with shorter overall survival and disease-free survival. 5-FU resistant HCT15 (HCT15/FU) cells expressed significantly higher levels of ECM1 relative to parental HCT15 cells. Changes in ECM1 expression altered the ability of both parental and HCT15/FU cells to tolerate the medication in vitro and in vivo via processes associated with apoptosis and EMT induction. From a mechanistic perspective, knocking down and overexpressing ECM1 in HCT15/FU and HCT15 cell lines inhibited and activated PI3K/AKT/GSK3β signaling, respectively. Accordingly, 5-FU-induced apoptotic activity and EMT phenotype changes were affected by treatment with PI3K/AKT agonists and inhibitors. Together, these data support a model wherein ECM1 regulates CRC resistance to 5-FU via PI3K/AKT/GSK3β pathway-mediated modulation of apoptotic resistance and EMT induction, highlighting ECM1 as a promising target for therapeutic intervention for efforts aimed at overcoming chemoresistance in CRC patients.

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“…The Use of Macropinocytosis-Inducing Carriers Despite breakthroughs in cancer therapies and the development of personalized medicine, chemoresistance remains a significant factor contributing to cancer mortality (Chern and Tai, 2020). However, macropinocytosis can increase the transport of anticancer agents into cancer cell lines, rendering chemotherapeutic drugs more effective against drug-resistant cells (Muley et al, 2020).…”

Section: Anticancer Therapies Targeting Macropinocytosis Exploitation...mentioning

confidence: 99%

The Role and Therapeutic Potential of Macropinocytosis in Cancer

et al. 2022

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Macropinocytosis, a unique endocytosis pathway characterized by nonspecific internalization, has a vital role in the uptake of extracellular substances and antigen presentation. It is known to have dual effects on cancer cells, depending on cancer type and certain microenvironmental conditions. It helps cancer cells survive in nutrient-deficient environments, enhances resistance to anticancer drugs, and promotes invasion and metastasis. Conversely, overexpression of the RAS gene alongside drug treatment can lead to methuosis, a novel mode of cell death. The survival and proliferation of cancer cells is closely related to macropinocytosis in the tumor microenvironment (TME), but identifying how these cells interface with the TME is crucial for creating drugs that can limit cancer progression and metastasis. Substantial progress has been made in recent years on designing anticancer therapies that utilize the effects of macropinocytosis. Both the induction and inhibition of macropinocytosis are useful strategies for combating cancer cells. This article systematically reviews the general mechanisms of macropinocytosis, its specific functions in tumor cells, its occurrence in nontumor cells in the TME, and its application in tumor therapies. The aim is to elucidate the role and therapeutic potential of macropinocytosis in cancer treatment.

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Adaptive response of resistant cancer cells to chemotherapy

Cited by 33 publications

References 256 publications

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses

ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction

The Role and Therapeutic Potential of Macropinocytosis in Cancer

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