Autophagy inhibition potentiates energy restriction-induced cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy. Additionally, ERMAs have been found to induce autophagy in cancer cells. The role of autophagy in cancer survival remains a subject of debate. Thus, it is crucial to ascertain whether ERMA-induced autophagy is a mechanism for cell survival or cell death in HCC. Our study aims to investigate the effect of autophagy inhibition on the survival of HCC cells treated with ERMAs while also examining the potential of combining an autophagy inhibitor such as spautin-1 with ERMAs to enhance HCC cell death. Our results suggest a cytoprotective role for ERMA-induced autophagy in HCC cells, as combining the autophagy inhibitor spautin-1 with ERMAs effectively suppressed ERMA-induced autophagy and synergistically enhanced their antitumor activity. The treatment combination promoted HCC death through apoptosis, cell cycle arrest, and inhibition of AKT and ERK activation, which are known to play a key role in cellular proliferation. Collectively, our findings highlight a potential strategy to combat HCC by combining energy restriction with autophagy inhibition.

Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines.

Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, wherein sorafenib, a multiple target tyrosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) database was utilized through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide metabolic pathways, energy production pathways and other pathways related to cancer aggressiveness, such as migration, proliferation and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified potential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug-resistant hepatocellular carcinoma.

The contribution of autophagy to drug resistance has been studied in several cancers. However, there is no clear evidence about the role of autophagy in the resistance to chemotherapy in cancers, such as hepatocellular carcinoma (HCC). HCC is characterized by a poor prognosis and limited therapeutic options. Moreover, the emergence of multidrug-resistance (MDR) hinders successful treatment. Therefore, understanding how autophagy is regulated in resistant HCC is essential for sensitizing this malignancy to chemotherapy. This work demonstrated that basal and induced autophagy differ between parental and resistant Hep3B cells. In optimum growth conditions, the basal level of autophagy was low in resistant Hep3B (Hep3B-R) cells compared to the wild-type Hep3B (Hep3B-P) cells. However, in metabolic or therapeutic stress conditions, the rate of autophagy flux was much faster in the resistant cells. The work also confirmed the pro-survival function of autophagy in HCC. Besides, it demonstrated that the autophagy inhibitor, spautin, acted synergistically with fingolimod (FTY720) to promote cell death. The combination treatment resulted in superior reactive oxygen species (ROS) production and significant induction of apoptosis. In addition, spautin potentiated the effect of FTY720 against cell survival pathways like the Akt and ERK. Interestingly, the results indicated that Hep3B-R cells were more sensitive to autophagy inhibition than their parental counterparts. Collectively, this work revealed that combining spautin with chemotherapeutic agents that induce cytoprotective autophagy such as FTY720 is a promising approach to overcome MDR in HCC.

Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors.

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines. Compound 1f showed the most potent activity, and it is more potent than sorafenib in 29 cancer cell lines of different types and more potent than SP600125 against almost all the tested cancer cell lines. It also exerted sub-micromolar IC50 values (0.54-0.98 µM) against nine cell lines. Moreover, the 23 target compounds were tested against Hep3B and HepG2 hepatocellular carcinoma cell lines, of which compounds 1b, 1c, and 1h showed the strongest anti-proliferative activity. The most potent anticancer compounds (1b, 1c, 1f, and 1h) demonstrated a high selectivity towards cancer cells vis-à-vis normal cells. Compounds1f and 1h induced apoptosis and mild necrosis upon testing against RPMI-8226 leukemia cells. Kinase profiling of this series led to the discovery of two potent and selective JNK3 inhibitors, compounds 1c and 1f with an IC50 values of 99.0 and 97.4 nM, respectively. Both compounds showed a good inhibitory effect against JNK3 kinase in the whole-cell NanoBRET assay. This finding was further supported through molecular modeling studies with the JNK3 binding site. Moreover, compounds 1c and 1f demonstrated a very weak activity against CYP 2D6, CYP 3A4, and hERG ion channels.

Cancer immunotherapy resistance: The impact of microbiome-derived short-chain fatty acids and other emerging metabolites.

The landscape of cancer therapy has undergone dramatic changes over the past decade. Immune checkpoint inhibitors (ICIs) among various cancer immunotherapies have transformed the treatment paradigm for cancer therapy and improved the survival of patients. Nevertheless, oncologists are faced with key challenges that need to be overcome, such as the unpredictability of patient response to these therapies and the many immune-related adverse effects (irAEs). One major factor contributing to patient response to treatment is the composition of their gut microbiota. Many studies reported the role of gut microbiota in modulating immunotherapy. In particular, microbiota-derived metabolites, mainly short-chain fatty acids (SCFAs), have been the highlights of many studies exploring the association between the gut microbiome and patient sensitivity to cancer immunotherapy. This review discusses the role of gut microbiota-derived metabolites on patient response to ICIs and their potential use as predictive biomarkers and therapeutic targets to fine-tune, regulate, and enhance cancer immunotherapy.

Tangeretin as an adjuvant and chemotherapeutic sensitizer against various types of cancers: a comparative overview.

OBJECTIVES: Cancer is a leading cause of disabling morbidities and death worldwide. Although there are various strategies for the management of cancer, the severe adverse effects negatively impact the patient's quality of life. In addition, the development of resistance limits the efficacy of many chemotherapeutics. Many natural agents are capable of reducing the adverse effects associated with chemotherapy and improving the therapeutic outcome. Tangeretin, a polymethoxy flavone, is one of the promising natural anticancer agents. KEY FINDINGS: Tangeretin not only targets various malignancies but also synergizes chemotherapeutic agents and reverses cancer resistance. Hence, the application of tangeretin as an adjuvant in cancer chemotherapy would be a promising strategy. SUMMARY: This work critically highlighted the proposed anticancer activity of tangeretin and discussed its potential combination with various chemotherapeutic agents. Additionally, it shed light on tangeretin chemical derivatives with improved pharmacokinetic and pharmacodynamic activity. Finally, this review described flavonoid biosynthetic pathways and how bioengineering can be employed to enhance the production yield of tangeretin. Thus, this work paves the way for the rational clinical utilization of tangeretin as a safe and effective adjuvant in chemotherapeutic protocols.

The dynamic association between COVID-19 and chronic disorders: An updated insight into prevalence, mechanisms and therapeutic modalities.

The devastating pandemic of coronavirus disease 2019 (COVID-19) has caused thousands of deaths and left millions of restless patients suffering from its complications. Increasing data indicate that the disease presents in a severe form in patients with pre-existing chronic conditions like cardiovascular diseases, diabetes, respiratory system diseases, and renal diseases. This denotes that these patients are more susceptible to COVID-19 and have higher mortality rates compared to patients with no comorbid conditions. Several factors can explain the heightened susceptibility and fatal presentation of COVID-19 in these patients, for example, the enhanced expression of the angiotensin-converting enzyme-2 (ACE2) in specific organs, cytokine storm, and drug interactions contribute to the increased morbidity and mortality. Adding to the findings that individuals with pre-existing conditions may be more susceptible to COVID-19, it has also been shown that COVID-19 can induce chronic diseases in previously healthy patients. Therefore, understanding the interlinked relationship between COVID-19 and chronic diseases helps in optimizing the management of susceptible patients. This review comprehensively described the molecular mechanisms that contribute to worse COVID-19 prognosis in patients with pre-existing comorbidities such as diabetes, cardiovascular diseases, respiratory diseases, gastrointestinal and renal diseases, blood disorders, autoimmune diseases, and finally, obesity. It also focused on how COVID-19 could, in some cases, lead to chronic conditions as a result of long-term multi-organ damage. Lastly, this work carefully discussed the tailored management plans for each specific patient population, aiming to achieve the best therapeutic outcome with minimum complications.

Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance.

Resistance to chemotherapeutic agents remains a major challenge in the fierce battle against cancer. Cancer stem cells (CSCs) are a small population of cells in tumors that possesses the ability to self-renew, initiate tumors, and cause resistance to conventional anticancer agents. Targeting this population of cells was proven as a promising approach to eliminate cancer recurrence and improve the clinical outcome. CSCs are less susceptible to death by classical anticancer agents inducing apoptosis. CSCs can be eradicated by ferroptosis, which is a non-apoptotic-regulated mechanism of cell death. The induction of ferroptosis is an attractive strategy to eliminate tumors due to its ability to selectively target aggressive CSCs. The current review critically explored the crosstalk and regulatory pathways controlling ferroptosis, which can selectively induce CSCs death. In addition, successful chemotherapeutic agents that achieve better therapeutic outcomes through the induction of ferroptosis in CSCs were discussed to highlight their promising clinical impact.

Tackling the cytokine storm in COVID-19, challenges and hopes.

The outbreak of Coronavirus disease 2019 (COVID-19) is the current world health concern, presenting a public health dilemma with ascending morbidity and mortality rates exceeding any previous viral spread, without a standard effective treatment yet. SARS-CoV-2 infection is distinguished with multiple epidemiological and pathological features, one of them being the elevated levels of cytokine release, which in turn trigger an aberrant uncontrolled response known as "cytokine storm". This phenomenon contributes to severe acute respiratory distress syndrome (ARDS), leading to pneumonia and respiratory failure, which is considered a major contributor to COVID-19-associated fatality rates. Taking into account that the vast majority of the COVID-19 cases are aggravated by the respiratory and multiorgan failure triggered by the sustained release of cytokines, implementing therapeutics that alleviate or diminish the upregulated inflammatory response would provide a therapeutic advantage to COVID-19 patients. Indeed, dexamethasone, a widely available and inexpensive corticosteroid with anti-inflammatory effects, has shown a great promise in reducing mortality rates in COVID-19 patients. In this review, we have critically compared the clinical impact of several potential therapeutic agents that could block or interfere with the cytokine storm, such as IL-1 inhibitors, IL-6 inhibitors, mast cell targeting agents, and corticosteroids. This work focused on highlighting and contrasting the current success and limitations towards the involvement of these agents in future treatment protocols.