The Role and Mechanism of Unfolded Protein Response Pathway in Tumor Drug Resistance

In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.

Distribution and drug resistance of pathogenic bacteria isolated from cancer hospital in 2013

Objective： To understand distribution and drug resistance of pathogenic bacteria from a specialized cancer hospital in 2013 in order to provide a basis for rational clinical antimicrobial agents. Methods： Pathogenic bacteria identification and drug sensitivity tests were performed with a VITEK 2 compact automatic identification system and data were analyzed using WHONET5.6 software.Results： Of the 1,378 strains tested, 980 were Gram-negative bacilli, accounting for 71.1%, in which Klebsiella pneumonia, Escherichia coli and Pseudomonas aeruginosa were the dominant strains. We found 328 Gram-positive coccus, accounting for 23.8%, in which the amount of Staphylococcus aureus was the highest. We identified 46 fungi, accounting for 4.1%. According to the departmental distribution within the hospital, the surgical departments isolated the major strains, accounting for 49.7%. According to disease types, lung cancer, intestinal cancer and esophagus cancer were the top three, accounting for 20.9%, 17.3% and 14.2%, respectively. No strains were resistant to imipenem, ertapenem or vancomycin.Conclusions： Pathogenic bacteria isolated from the specialized cancer hospital have different resistance rates compared to commonly used antimicrobial agents; therefore antimicrobial agents to reduce the morbidity and mortality of infections should be used.

Jaridon 6, a natural autophagy inducer, anti-gastric resistance in vivo and in vitro

OBJECTIVE Tumor resistant is the main cause leading to treatment failure.Tumor resistant is related to many aspect of tumor.Jaridon 6 is a new sesquiterpene come from Rabdosia rubescens extacted by our research team previously,have been tested having more obvious advantage than other anti-cancer drugs on tumor-resistant cells including a PTX-resistant gastric cancer cell.But how does the product work?In this paper,we have researched the effect and specific mechanism of Jaridon 6 on gastric-resistant.METHODS In the test,we have adopted vivo and vitro tests to identify the effect of Jaridon 6 on different gastric cancer-resistant cell.The MTT results,Flow test,Western blotting and nude test all verified the anti-cancer of Jaridon 6 on MGC803/PTX gastric resistant cell.We have also used scarifica⁃tion test and transwell tests and Western blotting to testify the inhibition action on EMT by Jaridon 6.The TEM and immu⁃nofluorescence tests have proved the induction autophagy of Jaridon 6.Immunohistochemical tests have been taken to assure the action of Jaridon 6 on EMT,autophagy and PI3K pathway in vivo.RESULTS Jaridon 6 could inhibite the gastric cancer resistant cell in vivo and in vitro.From the mechanism,the inhibiter of 3-MA or LY2940004 have proved the action on PI3K pathway and autophagy by Jaridon 6.Jaridon 6 could induce autophagy in tumor-resistant cells by inhibiting PI3K/AKT pathway.Except that,Jaridon 6 could inhibite the EMT of gastric cancer resistant cell.CONCLUSION Jaridon 6 could be considered for curing gastric cancer resistance,especially for PTX-resistance.Jaridon 6 is a natural autophagy inducer.

Histone modifications:Targeting head and neck cancer stem cells

Head and neck squamous cell carcinoma(HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells(CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of posttranslational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.

Phytic acid-modified CeO_(2) as Ca^(2+) inhibitor for a security reversal of tumor drug resistance

Ca^(2+)plays critical roles in the development of diseases,whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency.To solve this issue,with the help of Ca overexpressed tumor drug resistance model,the phytic acid(PA)-modified CeO_(2) nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca2+inhibitor to successfully reverse tumor drug resistance through Ca^(2+)negative regulation strategy.Using doxorubicin(Dox)as a model chemotherapeutic drug,the Ca^(2+)nano-inhibitors efficiently deprived intracellular excessive free Ca2+,suppressed P-glycoprotein(P-gp)expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells.This Ca^(2+)negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects.Besides,nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice.We anticipate that this safe and effective Ca^(2+)negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors,improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca^(2+) associated diseases.

Imaging Tumors Resistance to Chemotherapy Circumvented with Nanoparticle

Malignant tumor is one of the most notorious diseases devastating human lives.

Does burning fat make tumor immune hot? Discovery of cD47 overexpression by radiation induced fatty acid oxidation

Although extensively studied,it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy.Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors.However,accumulating evidence indicates that in addition to the rudimentary glycolytic pathway,tumor cells are capable of reactivating mitochondrial OxPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation.Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis.Interestingly,data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

A tumor-penetrable drug nanococktail made from human histones for interventional nucleus-targeted chemophotothermal therapy of drug-resistant tumors

Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.

Major hurdles of immune-checkpoint inhibitors in pancreatic ductal adenocarcinoma

In 2030,pancreatic ductal adenocarcinoma(PDAC)will become the second leading cause of cancer-related mortality in the world.Unfortunately,neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low.PDAC is notorious for its immuneresistant features and unique genomic landscape facilitating tumor escape from immunosurveillance.Novel immune-checkpoint inhibitors(ICI)failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials.In this paper,we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.