CDK inhibitors from past to present: A new wave of cancer therapy.

Deregulation of the cell cycle machinery, which has been linked to dysregulation of cyclin-dependent kinases (CDKs), is a defining characteristic of cancer, eventually promoting abnormal proliferation that feeds tumorigenesis and disease development. In this regard, several CDK inhibitors (CDKIs) have been developed during the last few decades (1st, 2nd, and 3rd generation CDKIs) to inhibit cancer cell proliferation. 1st and 2nd generation CDKIs have not received much clinical attention for the treatment of cancer patients because of their limited specificity and high toxicity. However, the recent development of combination strategies allowed us to reduce the toxicity and side effects of these CDKIs, paving the way for their potential application in clinical settings. The 3rd generation CDKIs have yielded the most promising results at the preclinical and clinical levels, propelling them into the advanced stages of clinical trials against multiple malignancies, especially breast cancer, and revolutionizing traditional treatment strategies. In this review, we discuss the most-investigated candidates from the 1st, 2nd, and 3rd generations of CDKIs, their basic mechanisms of action, the reasons for their failure in the past, and their current clinical development for the treatment of different malignancies. Additionally, we briefly highlighted the most recent clinical trial results and advances in the development of 3rd generation FDA-approved selective CDK4/6 inhibitors that combat the most prevalent cancer. Overall, this review will provide a thorough knowledge of CDKIs from the past to the present, allowing researchers to rethink and develop innovative cancer therapeutic regimens.

Nanotechnology-based approaches overcome lung cancer drug resistance through diagnosis and treatment.

Lung cancer continues to be a malignant tumor with high mortality. Two obstacles interfere with curative therapy of lung cancer: (i) poor diagnosis at the early stages, as symptoms are not specific or asymptomatic; and (ii) invariably emerging drug resistance after treatment. Some factors contributing to drug resistance include preexisting genetic/genomic drug-resistant alteration(s); activation of adaptive drug resistance pathways; remodeling of the tumor microenvironment; and pharmacological mechanisms or activation of drug efflux pumps. Despite the mechanisms explored to better understand drug resistance, a gap remains between molecular understanding and clinical application. Therefore, facilitating the translation of basic science into the clinical setting is a great challenge. Nanomedicine has emerged as a promising tool for cancer treatment. Because of their excellent physicochemical properties and enhanced permeability and retention effects, nanoparticles have great potential to revolutionize conventional lung cancer diagnosis and combat drug resistance. Nanoplatforms can be designed as carriers to improve treatment efficacy and deliver multiple drugs in one system, facilitating combination treatment to overcome drug resistance. In this review, we describe the difficulties in lung cancer treatment and review recent research progress on nanoplatforms aimed at early diagnosis and lung cancer treatment. Finally, future perspectives and challenges of nanomedicine are also discussed.

Downregulation of Ambra1 by altered DNA methylation exacerbates dopaminergic neuron damage in a fenpropathrin-induced Parkinson-like mouse model.

Fenpropathrin (Fen), a volatile pyrethroid insecticide, is used widely for agricultural applications and has been reported to increase the risk of Parkinson's disease (PD). However, the molecular basis, underlying mechanisms, and pathophysiology of Fen-exposed Parkinsonism remain unknown. Recent studies have revealed epigenetic mechanisms underlying PD-related pathway regulation, including DNA methylation. Epigenetic mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. After whole-genome bisulfite sequencing (WGBS) of midbrain tissues from a Fen-exposed PD-like mouse model, we performed an association analysis of DNA methylation and gene expression. Then we successfully screened for the DNA methylation differential gene Ambra1, which is closely related to PD. The hypermethylation-low expression Ambra1 gene aggravated DA neuron damage in vitro and in vivo through the Ambra1/Parkin/LC3B-mediated mitophagy pathway. We administered 5-aza-2'-deoxycytidine (5-Aza-dC) to upregulate Ambra1 expression, thereby reducing Ambra1-mediated mitophagy and protecting DA neurons against Fen-induced damage. In conclusion, these findings elucidate the potential function of Ambra1 under the regulation of DNA methylation, suggesting that the inhibition of DNA methylation may alleviate Fen-exposed neuron damage.

New opportunities and challenges of venom-based and bacteria-derived molecules for anticancer targeted therapy.

Due to advances in detection and treatment of cancer, especially the rise in the targeted therapy, the five-year relative survival rate of all cancers has increased significantly. However, according to the analysis of the survival rate of cancer patients in 2019, the survival rate of most cancers is still less than five years. Therefore, to combat complex cancer and further improve the 5-year survival rate of cancer patients, it is necessary to develop some new anticancer drugs. Because of the adaptive evolution of toxic species for millions of years, the venom sac is a "treasure bank", which has millions of biomolecules with high affinity and stability awaiting further development. Complete utilization of venom-based and bacteria-derived drugs in the market is still staggering because of incomplete understanding regarding their mode of action. In this review, we focused on the currently identified targets for anticancer effects based on venomous and bacterial biomolecules, such as ion channels, membrane non-receptor molecules, integrins, and other related target molecules. This review will serve as the key for exploring the molecular mechanisms behind the anticancer potential of venom-based and bacteria-derived drugs and will also lay the path for the development of anticancer targeted therapy.

Multidimensional role of bacteria in cancer: Mechanisms insight, diagnostic, preventive and therapeutic potential.

The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.

Targeting lactate-related cell cycle activities for cancer therapy.

Lactate has long been considered as a metabolic by-product of aerobic glycolysis for cancer. However, more and more studies have shown that lactate can regulate cancer progression via multiple mechanisms such as cell cycle regulation, immune suppression, energy metabolism and so on. A recent discovery of lactylation attracted a lot of attention and is already a hot topic in the cancer field. In this review, we summarized the latest functions of lactate and its underlying mechanisms in cancer. We also included our analysis of protein lactylation in different rat organs and compared them with other published lactylation data. The unresolved challenges in this field were discussed, and the potential application of these new discoveries of lactate-related cell cycle activities for cancer target therapy was speculated.

Inhibition of bladder cancer growth with homoharringtonine by inactivating integrin α5/ß1-FAK/Src axis: A novel strategy for drug application.

The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/ß1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer.

Scorpion venom peptides: Molecular diversity, structural characteristics, and therapeutic use from channelopathies to viral infections and cancers.

Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources.

A novel combination treatment of antiADAM17 antibody and erlotinib to overcome acquired drug resistance in non-small cell lung cancer through the FOXO3a/FOXM1 axis.

After the identification of specific epidermal growth factor receptor (EGFR)-activating mutations as one of the most common oncogenic driver mutations in non-small cell lung cancer (NSCLC), several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) with different clinical efficacies have been approved by various health authorities in the last two decades in targeting NSCLC harboring specific EGFR-activating mutations. However, most patients whose tumor initially responded to the first-generation EGFR-TKI developed acquired resistance. In this study, we developed a novel combination strategy, "antiADAM17 antibody A9(B8) + EGFR-TKIs", to enhance the efficacy of EGFR-TKIs. The addition of A9(B8) was shown to restore the effectiveness of erlotinib and overcome acquired resistance. We found that when A9(B8) antibody was treated with erlotinib or gefitinib, the combination treatment synergistically increased apoptosis in an NSCLC cell line and inhibited tumor growth in vivo. Interestingly, the addition of A9(B8) could only reduce the survival of the erlotinib-resistant NSCLC cell line and inhibit the growth of erlotinib-resistant tumors in vivo but not gefitinib-resistant cells. Furthermore, we revealed that A9(B8) overcame erlotinib resistance through the FOXO3a/FOXM1 axis and arrested the cell cycle at the G1/S phase, resulting in the apoptosis of cancer cells. Hence, this study establishes a novel, promising strategy for overcoming acquired resistance to erlotinib through the FOXO3a/FOXM1 axis by arresting the cell cycle at the G1/S phase.

The tick saliva peptide HIDfsin2 promotes the tick-borne virus SFTSV replication in vitro by enhancing p38 signal pathway.

Pathogens co-evolved with ticks to facilitate blood collection and pathogen transmission. Although tick saliva was recently found to be rich in bioactive peptides, it is still elusive which saliva peptide promotes virus transmission and which pathways are invovled. Here, we used a saliva peptide HIDfsin2 and a severe fever with thrombocytopenia syndrome virus (SFTSV) both carried by the tick Haemaphysalis longicornis to elucidate the relationship between tick saliva components and tick-borne viruses. HIDfsin2 was found to promote the replication of SFTSV in a dose-dependent manner in vitro. HIDfsin2 was further revealed to MKK3/6-dependently magnify the activation of p38 MAPK. The overexpression, knockdown and phosphorylation site mutation of p38α indicated that p38 MAPK activation facilitated SFTSV infection in A549 cells. Moreover, the blockade of p38 MAPK activation significantly suppressed SFTSV replication. Differently, HIDfsin2 or pharmacological inhibition of p38 MAPK activation had no effect on a mosquito-borne Zika virus (ZIKV). All these results showed that HIDfsin2 specifically promoted SFTSV replication through the MKK3/6-dependent enhancement of p38 MAPK activation. Our study provides a new perspective on the transmission of tick-borne viruses under natural conditions, and supports that the blockade of p38 MAPK activation can be a promising strategy against the mortal tick-borne virus SFTSV.

p38 activation and viral infection.

Viruses completely rely on the energy and metabolic systems of host cells for life activities. Viral infections usually lead to cytopathic effects and host diseases. To date, there are still no specific clinical vaccines or drugs against most viral infections. Therefore, understanding the molecular and cellular mechanisms of viral infections is of great significance to prevent and treat viral diseases. A variety of viral infections are related to the p38 MAPK signalling pathway, and p38 is an important host factor in virus-infected cells. Here, we introduce the different signalling pathways of p38 activation and then summarise how different viruses induce p38 phosphorylation. Finally, we provide a general summary of the effect of p38 activation on virus replication. Our review provides integrated data on p38 activation and viral infections and describes the potential application of targeting p38 as an antiviral strategy.

The intricate roles of RCC1 in normal cells and cancer cells.

RCC1 (regulator of chromosome condensation 1) is a highly conserved chromatin-binding protein and the only known guanine-nucleotide exchange factor of Ran (a nuclear Ras homolog). RCC1 plays an essential role in the regulation of cell cycle-related activities such as nuclear envelope formation, nuclear pore complex and spindle assembly, and nucleocytoplasmic transport. Over the last decade, increasing evidence has emerged highlighting the potential relevance of RCC1 to carcinogenesis, especially cervical, lung, and breast cancer. In this review, we briefly discuss the roles of RCC1 in both normal and tumor cells based on articles published in recent years, followed by a brief overview of future perspectives in the field.

Leukocyte Tetraspanin CD53 Restrains α3 Integrin Mobilization and Facilitates Cytoskeletal Remodeling and Transmigration in Mice.

The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53-/- mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53-/- neutrophils revealed no alteration in expression of ß2 integrins, whereas L-selectin was almost completely absent from Cd53-/- neutrophils. In addition, Cd53-/- neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53-/- mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.

Synergistic combination of targeted nano-nuclear-reactors and anti-PD-L1 nanobodies evokes persistent T cell immune activation for cancer immunotherapy.

BACKGROUND: Antitumor T cell immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the tumor microenvironment (TME) is characterized by the low immunogenicity, hypoxia, and immunosuppressive condition that dramatically limit effective T cell immunotherapy. Thus, an ideal immunotherapy strategy that is capable of reversing the immunosuppressive TME is highly imperative. RESULTS: In this article, we reported that Fe-doped and doxorubicin (DOX) loaded HA@Cu2-XS-PEG (PHCN) nanomaterials were rationally designed as targeted Fe-PHCN@DOX nano-nuclear-reactors, which evoked persistent T cell immune response together with anti-PD-L1 nanobodies. It was confirmed that nano-nuclear-reactors displayed strong nanocatalytic effect for effective antitumor effects. Consequently, they maximized the immunogenic cell death (ICD) effect for antigen presentation and then stimulated T cell activation. In addition, Fe-PHCN@DOX could reprogram M2-phenotype tumor-associated macrophages (TAMs) into M1-phenotype TAMs by relieving tumor hypoxia. Meanwhile, blockade of the anti-PD-L1 nanobody promoted T cell activation through targeting the PD-1/PD-L1 immunosuppressive pathway. Notably, in vivo tumor therapy verified that this nano-nuclear-reactor could be used as an excellent immunotherapy nanoplatform for tumor eradication and metastasis prevention with nanobody. CONCLUSIONS: Our findings demonstrated that nano-nuclear-reactors in combination with nanobody could evoke persistent T cell immune activation, suggesting them potential as a promising immunotherapy option for reversing immunosuppressive immune-cold tumors.

Boronate ester bond-based potentiometric aptasensor for screening carcinoembryonic antigen-glycoprotein using nanometer-sized CaCO3 with ion-selective electrode.

Phenylboronic acid-functionalized nanometer-sized CaCO3 particles (PBA-CaCO3) were designed to determine the carcinoembryonic antigen (CEA) glycoprotein with a portable Ca2+ ion-selective electrode (Ca-ISE) through a typical boronate ester bond. CaCO3 nanospheres were conjugated to 3-aminophenylboronic acid by amine-epoxy reaction, whereas target CEA was captured into the aptasensing interface by the immobilized thiolated aptamer on gold substrate. Upon PBA-CaCO3 introduction, 3-aminophenylboronic acid labeled to CaCO3 microsphere specifically recognized with CEA glycoprotein based on sugar-boronic acid interaction to form a sandwiched complex. The carried CaCO3 was dissolved under acidic conditions to release Ca2+ ion with a portable Ca-ISE readout. Thanks to the specific boronate ester bond between PBA and 1,2-diols, the synthesized PBA-CaCO3 exhibited good conjugation properties for CEA glycoprotein. Under optimum conditions, Ca-ISE-based aptasensing platform exhibited good electrode potential response for evaluation of target CEA, and allowed detection of CEA at a concentration as low as 7.3 pg mL-1. Importantly, Ca-ISE-based aptasensing system is readily extended to detect other disease-related glycoproteins by controlling the corresponding aptamer.

Development of Marine-Derived Compounds for Cancer Therapy.

Cancer has always been a threat to human health with its high morbidity and mortality rates. Traditional therapy, including surgery, chemotherapy and radiotherapy, plays a key role in cancer treatment. However, it is not able to prevent tumor recurrence, drug resistance and treatment side effects, which makes it a very attractive challenge to search for new effective and specific anticancer drugs. Nature is a valuable source of multiple pharmaceuticals, and most of the anticancer drugs are natural products or derived from them. Marine-derived compounds, such as nucleotides, proteins, peptides and amides, have also shed light on cancer therapy, and they are receiving a fast-growing interest due to their bioactive properties. Their mechanisms contain anti-angiogenic, anti-proliferative and anti-metastasis activities; cell cycle arrest; and induction of apoptosis. This review provides an overview on the development of marine-derived compounds with anticancer properties, both their applications and mechanisms, and discovered technologies.

Handheld pH meter-assisted immunoassay for C-reactive protein using glucose oxidase-conjugated dendrimer loaded with platinum nanozymes.

A simple and feasible pH meter-based immunoassay is reported for detection of C-reactive protein (CRP) using glucose oxidase (GOD)-conjugated dendrimer loaded with platinum nanozyme. Initially, platinum nanozymes were loaded into the dendrimers through an in situ synthetic method. Then, GOD and monoclonal anti-CRP antibody with a high molar ratio were covalently conjugated onto carboxylated dendrimers via typical carbodiimide coupling. The immunoreaction was carried out with a competitive mode in a CRP-coated microplate. Along with formation of immunocomplex, the added glucose was oxidized into gluconic acid and hydrogen peroxide by GOD, and the latter was further decomposed by platinum nanozyme, thus accelerating chemical reaction in the positive direction. The produced gluconic acid changed the pH of detection solution, which was determined using a handheld pH meter. Under optimum conditions, the pH meter-based immunoassay gave a good signal toward target CRP from 0.01 to 100 ng mL-1. The limit of detection was 5.9 pg mL-1. An intermediate precision ≤ 11.2% was acquired with batch-to-batch identification. No nonspecific adsorption was observed during a series of procedures to detect target CRP, and the cross-reaction against other biomarkers was very low. Importantly, our system gave well-matched results for analysis of human serum samples relative to a referenced ELISA kit.Graphical abstract.

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues.

Temporin is an antimicrobial peptide (AMP) family discovered in the skin secretion of ranid frog that has become a promising alternative for conventional antibiotic therapy. Herein, a novel temporin peptide, Temporin-PF (TPF), was successfully identified from Pelophylax fukienensis. It exhibited potent activity against Gram-positive bacteria, but no effect on Gram-negative bacteria. Additionally, TPF exhibited aggregation effects in different solutions. Three analogs were further designed to study the relationship between the aggregation patterns and bioactivities, and the MD simulation was performed for revealing the pattern of the peptide assembly. As the results showed, all peptides were able to aggregate in the standard culture media and salt solutions, especially CaCl2 and MgCl2 buffers, where the aggregation was affected by the concentration of the salts. MD simulation reported that all peptides were able to form oligomers. The parent peptide assembly depended on the hydrophobic interaction via the residues in the middle domain of the sequence. However, the substitution of Trp/D-Trp resulted in an enhanced inter-peptide interaction in the zipper-like domain and eliminated overall biological activities. Our study suggested that introducing aromaticity at the zipper-like domain for temporin may not improve the bioactivities, which might be related to the formation of aggregates via the inter-peptide contacts at the zipper-like motif domain, and it could reduce the binding affinity to the lipid membrane of microorganisms.

DNA replication licensing proteins: Saints and sinners in cancer.

DNA replication is all-or-none process in the cell, meaning, once the DNA replication begins it proceeds to completion. Hence, to achieve maximum control of DNA replication, eukaryotic cells employ a multi-subunit initiator protein complex known as "pre-replication complex or DNA replication licensing complex (DNA replication LC). This complex involves multiple proteins which are origin-recognition complex family proteins, cell division cycle-6, chromatin licensing and DNA replication factor 1, and minichromosome maintenance family proteins. Higher-expression of DNA replication LC proteins appears to be an early event during development of cancer since it has been a common hallmark observed in a wide variety of cancers such as oesophageal, laryngeal, pulmonary, mammary, colorectal, renal, urothelial etc. However, the exact mechanisms leading to the abnormally high expression of DNA replication LC have not been clearly deciphered. Increased expression of DNA replication LC leads to licensing and/or firing of multiple origins thereby inducing replication stress and genomic instability. Therapeutic approaches where the reduction in the activity of DNA replication LC was achieved either by siRNA or shRNA techniques, have shown increased sensitivity of cancer cell lines towards the anti-cancer drugs such as cisplatin, 5-Fluorouracil, hydroxyurea etc. Thus, the expression level of DNA replication LC within the cell determines a cell's fate thereby creating a paradox where DNA replication LC acts as both "Saint" and "Sinner". With a potential to increase sensitivity to chemotherapy drugs, DNA replication LC proteins have prospective clinical importance in fighting cancer. Hence, in this review, we will shed light on importance of DNA replication LC with an aim to use DNA replication LC in diagnosis and prognosis of cancer in patients as well as possible therapeutic targets for cancer therapy.