Combination Anticancer Therapy Research Articles

Nucleus-targeting DNase I self-assembly delivery system guided by pirarubicin for programmed multi-drugs release and combined anticancer therapy

The cell nucleus serves as the pivotal command center of living cells, and delivering therapeutic agents directly into the nucleus can result in highly efficient anti-tumor eradication of cancer cells. However, nucleus-targeting drug delivery is very difficult due to the presence of numerous biological barriers. Here, three antitumor drugs (DNase I, ICG: indocyanine green, and THP: pirarubicin) were sequentially triggered protein self-assembly to produce a nucleus-targeting and programmed responsive multi-drugs delivery system (DIT). DIT consisted of uniform spherical particles with a size of 282 ± 7.7 nm. The acidic microenvironment of tumors and near-infrared light could successively trigger DIT for the programmed release of three drugs, enabling targeted delivery to the tumor. THP served as a nucleus-guiding molecule and a chemotherapy drug. Through THP-guided DIT, DNase I was successfully delivered to the nucleus of tumor cells and killed them by degrading their DNA. Tumor acidic microenvironment had the ability to induce DIT, leading to the aggregation of sufficient ICG in the tumor tissues. This provided an opportunity for the photothermal therapy of ICG. Hence, three drugs were cleverly combined using a simple method to achieve multi-drugs targeted delivery and highly effective combined anticancer therapy.

Common predictors of cervical cancer related mortality in Ethiopia. A systematic review and meta-analysis

BackgroundCervical cancer accounts for 7.5% of all female cancer related deaths worldwide; peaking between the ages of 35 and 65, and not only kills young women but also destroys families with young children.ObjectiveThis review was intended to measure national level magnitude and the most common predictors of cervical cancer related mortality in Ethiopia.MethodsCommon Public databases like Science Direct, Embase, the Cochrane Library, and PubMed were thoroughly searched. The STATA 14 and Rev-Manager 5.3 statistical software packages were used for analysis, as well as a standardized data abstraction tool created in Microsoft Excel. The Cochrane Q-test statistics and the I2 test were used to assess non-uniformity. The pooled magnitude and predictors of cervical cancer related mortality were estimated using fixed-effect and random-effect models, respectively.ResultThe pooled mortality among cervical cancer patients was estimated that 16.39% at 95% confidence level fall in 13.89–18.88% in Ethiopia. The most common predictors of cervical cancer related mortality were late diagnosed, radiation therapy alone, and Being anemic were identified by this review. Among cervical cancer treatment modalities effectiveness of surgery with adjuvant therapy was also approved in this meta-analysis.Conclusion and recommendationIn this study high cervical cancer-related mortality was reported as compared to national strategies to alleviate cervical cancer related mortality. Advanced implementation of cervical cancer screening at the national level for early diagnosis, anaemia detection, and combination anticancer therapy during initiation, as well as combination therapy, is critical to improve cervical cancer patient survival and decreasing mortality rates.

Combined Anticancer Therapy for Prostate Cancer - Literature Review

Prostate cancers represent a significant health problem, and their etiology is complex and multifaceted. It is estimated that in 2018, 1.3 million new cases and 359,000 deaths due to prostate cancer were diagnosed. They constitute the second most common group of cancers and the fifth most common cause of cancer-related deaths in men worldwide. The present study encompasses a literature review aimed at conducting an analysis of the potential of combined anticancer therapy as a prospective method for enhancing treatment efficacy, minimizing side effects, and improving long-term survival outcomes for prostate cancer patients. Combinations of compounds such as sunitinib with docetaxel, carboplatin with paclitaxel, estramustine or flutamide with luteinizing hormone-releasing hormone agonists, as well as docetaxel in conjunction with dexamethasone and octreotide, have demonstrated synergistic effects and an augmentation of therapeutic effectiveness. It is noteworthy to emphasize the potential enhancement of docetaxel's anticancer activity with concurrent administration of dexamethasone and octreotide, as well as combined therapy involving docetaxel, prednisone, and curcumin.

Secretion of Sphinganine by Drug-Induced Cancer Cells and Modified Mimetic Sphinganine (MMS) as c-Src Kinase Inhibitor.

Cancer cells exhibit selective metabolic reprogramming to promote proliferation, invasiveness, and metastasis. Sphingolipids such as sphingosine and sphinganine have been reported to modulate cell death processes in cancer cells. However, the potential of extracellular sphinganine and its mimetic compounds as inducers of cancer cell death has not been thoroughly investigated. We obtained extracellular conditioned medium from HCT-116 cells treated with the previously reported anticancer composition, goat urine DMSO fraction (GUDF). The extracellular metabolites were purified using a novel and in-house developed vertical tube gel electrophoresis (VTGE) technique and identified through LC-HRMS. Extracellular metabolites such as sphinganine, sphingosine, C16 sphinganine, and phytosphingosine were screened for their inhibitory role against intracellular kinases using molecular docking. Molecular dynamics (MD) simulations were performed to study the inhibitory potential of a novel designed modified mimetic sphinganine (MMS) (Pubchem CID: 162625115) upon c-Src kinase. Furthermore, inhibitory potential and ADME profile of MMS was compared with luteolin, a known c-Src kinase inhibitor. Data showed accumulation of sphinganine and other sphingolipids such as C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0) in the extracellular compartment of GUDF-treated HCT-116 cells. Molecular docking projected c-Src kinase as an inhibitory target of sphinganine. MD simulations projected MMS with strong (-7.1 kcal/mol) and specific (MET341, ASP404) binding to the inhibitory pocket of c-Src kinase. The projected MMS showed comparable inhibitory role and acceptable ADME profile over known inhibitors. In summary, our findings highlight the significance of extracellular sphinganine and other sphingolipids, including C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0), in the context of drug-induced cell death in HCT-116 cancer cells. Furthermore, we demonstrated the importance of extracellular sphinganine and its modified mimetic sphinganine (MMS) as a potential inhibitor of c-Src kinase. These findings suggest that MMS holds promise for future applications in targeted and combinatorial anticancer therapy.

Clinicopathological features of kidney injury in patients receiving immune checkpoint inhibitors (ICPi) combined with anti-vascular endothelial growth factor (anti-VEGF) therapy

BackgroundImmune checkpoint inhibitor (ICPi) combined with anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various malignancies. However, the combination might be associated with increased risk...

An interpretable artificial intelligence framework for designing synthetic lethality-based anti-cancer combination therapies

IntroductionSynthetic lethality (SL) provides an opportunity to leverage different genetic interactions when designing synergistic combination therapies. To further explore SL-based combination therapies for cancer treatment, it is important to identify and mechanistically characterize more SL interactions. Artificial intelligence (AI) methods have recently been proposed for SL prediction, but the results of these models are often not interpretable such that deriving the underlying mechanism can be challenging. ObjectivesThis study aims to develop an interpretable AI framework for SL prediction and subsequently utilize it to design SL-based synergistic combination therapies. MethodsWe propose a knowledge and data dual-driven AI framework for SL prediction (KDDSL). Specifically, we use gene knowledge related to the SL mechanism to guide the construction of the model and develop a method to identify the most relevant gene knowledge for the predicted results. ResultsExperimental and literature-based validation confirmed a good balance between predictive and interpretable ability when using KDDSL. Moreover, we demonstrated that KDDSL could help to discover promising drug combinations and clarify associated biological processes, such as the combination of MDM2 and CDK9 inhibitors, which exhibited significant anti-cancer effects in vitro and in vivo.ConclusionThese data underscore the potential of KDDSL to guide SL-based combination therapy design. There is a need for biomedicine-focused AI strategies to combine rational biological knowledge with developed models.

"Combination Anti-Cancer Drugs Therapy: A Strategic Approach for Effective Treatment and Management of Cancer"

"Combination Anti-Cancer Drugs Therapy: A Strategic Approach for Effective Treatment and Management of Cancer"

Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy.

Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.

Ce6 nanoassemblies: Molecular mechanism and strategies for combinational anticancer therapy

AbstractNowadays, cancer has become the leading cause of death worldwide, driving the need for effective therapeutics to improve patient prognosis. Photodynamic therapy (PDT) has been widely applied as an antitumor modality, owing to its minimal invasiveness, localized tumor damage, and high safety profile. However, its efficacy is limited by poor stability of photosensitizers, inadequate tumor accumulation, and a complex tumor microenvironment. To overcome these challenges, extensive endeavors have been made to explore the co‐assembly of the widely used photosensitizer chlorin e6 (Ce6) with various functional small molecules to enhance pharmacodynamic activity. This review provides a comprehensive overview of current studies on Ce6‐based nanoparticles for effective PDT and precise delivery of functional molecules. The self‐assembly mechanism will be discussed in detail, with a focus on potential strategies for combinational therapy with PDT.

Spider diagram with greenness evaluation metrics for assessing the new synchronous spectrofluorimetric determination of bicalutamide and resveratrol in human plasma.

A simple, selective, and eco-friendly synchronous fluorescence approach was introduced for the first time for the concurrent estimation of the anticancer combination therapy of bicalutamide and resveratrol. The method relies on measuring the synchronous fluorescence spectra of bicalutamide and resveratrol at 269 and 320 nm, respectively, using Δλ of 60 nm with ethanol as a green diluting solvent. The procedure was optimized, and the method was then fully validated. Excellent linearity (R2  > 0.999) with very low detection limits (0.044 and 2.001 ng/ml) were obtained for both drugs, allowing for their analysis in human plasma. The green profile of the suggested approach was evaluated using the green solvents selecting tool (GSST), spider diagram for greenness index assessment, green analytical process index (GAPI), and Analytical GREEnness (AGREE) metric tools. These assessment metrics confirmed that the developed approach met the maximum number of green requirements, recommending its application as a green substitute for the regular analysis of the concerned drugs in human plasma. The simplicity of sample measurement enables and substantially accelerates the analysis, resulting in lower costs, enhanced procedure accuracy, and lower environmental effect.

Mn-Si-based nanoparticles-enhanced inhibitory effect on tumor growth and metastasis in photo-immunotherapy

The anticancer effect of phototherapy has been limited by some factors, including the easy degradation of photo agents, the complex tumor microenvironment, and the limited immune activation capacity, which impedes its efficiency in inhibiting tumor growth and tumor metastasis. Herein, Mn-doped mesoporous silica nanoparticles were synthesized to load the photo agent of IR 780, which were further coated with Mn (IMM). Notably, the combination of IMM and an 808 nm laser irradiation simultaneously inhibited the growth of primary tumors and distant untreated tumors in a bilateral animal model, which could be attributed to the protection of IMM to IR 780, the regulation functions to the tumor microenvironment, as well as the enhanced immune activation capacity. This work highlighted an alternative strategy for enhancing the inhibitory effect on both tumor growth and tumor metastasis in the combinational anticancer therapy of phototherapy and immunotherapy (photo-immunotherapy).

Novel construction of multifunctional photo-responsive and nucleic acid-triggered doxorubicin-releasing liposomes for cancer therapy

All-in-one nano theranostics integrating accurate diagnosis and combined therapy is promising for high-efficacy tumor treatment and receiving significant attention. In this study, we develop photo-controlled release liposomes with nucleic acid-triggered fluorescence and photoactivity for tumor imaging and synergistic antitumor therapy. Copper phthalocyanine as a photothermal agent is fused into lipid layers to prepare liposomes encapsulating cationic zinc phthalocyanine ZnPc(TAP)412+ and doxorubicin, followed by the modification of RGD peptide on the surface to obtain the final product RGD-CuPc:ZnPc(TAP)412+:DOX@LiPOs (RCZDL). RCZDL possesses favorable stability, significant photothermal effect, and photo-controlled release function through the characterization of physicochemical properties. It is shown that the fluorescence and ROS generation could be turned on by intracellular nucleic acid after illumination. RCZDL exhibits synergistic cytotoxicity, increased apoptosis, and significantly promoted cell uptake. Subcellular localization analysis indicates that ZnPc(TAP)412+ tends to be distributed in the mitochondria of HepG2 cells treated with RCZDL after exposure to light. The results of experiments in vivo on H22 tumor-bearing mice demonstrate that RCZDL had excellent tumor targeting, a prominent photothermal effect at the tumor sites, and synergistic antitumor efficiency. More importantly, little RCZDL has been found to be accumulated in the liver, and most were quickly metabolized by the liver. The results confirm that the proposed new intelligent liposomes provide a simple and cost-effective way for tumor imaging and combinatorial anticancer therapy.

Fine-Tuned Polymer Nanoassembly for Codelivery of Chemotherapeutic Drug and siRNA.

Successful clinical application of siRNA to liver-associated diseases reinvigorates the RNAi therapeutics and delivery vectors, especially for anticancer combination therapy. Fine tuning of copolymer-based assembly configuration is highly important for a desirable synergistic cancer cell-killing effect via the codelivery of chemotherapeutic drug and siRNA. Herein, an amphiphilic triblock copolymer methoxyl poly(ethylene glycol)-block-poly(L-lysine)-block-poly(2-(diisopropyl amino)ethyl methacrylate) (abbreviated as mPEG-PLys-PDPA or PLD) consisting of a hydrophilic diblock mPEG-PLys and a hydrophobic block PDPA is synthesized. Three distinct assemblies (i.e., nanosized micelle, nanosized polymersome, and microparticle) are acquired, along with the increase in PDPA block length. Furthermore, the as-obtained polymersome can efficiently codeliver doxorubicin hydrochloride (DOX) as a hydrophilic chemotherapeutic model and siRNA against ADP-ribosylation factor 6 (siArf6) as an siRNA model into cancer cell via lysosomal pH-triggered payload release. PC-3 prostate cell is synergistically killed by the DOX- and siArf6-coloading polymersome (namely PLD@DOX/siArf6). PLD@DOX/siArf6 may serve as a robust nanomedicine for anticancer therapy.

SiRNA-E6 sensitizes HPV-16-related cervical cancer through Oxaliplatin: an in vitro study on anti-cancer combination therapy

BackgroundPersistent infection with high-risk Human papillomaviruses (HPV), such as hr-HPV-16 and hr-HPV-18, lead to cervical cancer, the fourth most common cancer in the world. In the present study, we investigated the alteration of E6 oncogene expression by E6-specific short interfering RNA (siRNA) combined with Oxaliplatin.MethodsThe cervical cancer cell line, CaSki, was transfected with E6-siRNA, then treated with Oxaliplatin. The cellular genes, such as p53, MMP9, Nanog, and caspases expression, were assessed by quantitative real-time PCR. The cell death rate, cell cycle, and cell viability were assessed by Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, colony formation assay and scratch test determined the stemness ability and cell metastasis, respectively.ResultsCombination therapy increased the re-expression of genes involved in the p53-dependent apoptosis pathway (increase in apoptosis to 44.2%), and reduced stemness and metastasis ability compared to either siRNA or Oxaliplatin monotherapy. Together, our results demonstrate that E6-siRNA and Oxaliplatin combination increased the cervical cancer cells’ sensitivity to Oxaliplatin and decreased the survival rate, proliferation, and metastasis, and consequently escalated apoptosis rate, induced cell cycle arrest in the sub-G1 stage, and reduced the chemotherapy drug dosage.ConclusionInhibition of E6 oncogene expression and subsequent E6-siRNA with Oxaliplatin combination therapy could be a novel strategy for cervical cancer treatment.Graphical

Лептоменингеальный канцероматоз при BRCA1-ассоциированном раке яичников

Leptomeningeal carcinomatosis (LMC) in ovarian cancer is a rare complication of malignant gynecological disease, which is characterized by the spread of tumor cells through the cerebrospinal fluid to the membranes surrounding the brain and spinal cord. The cause of rare involvement of central nervous system (CNS) meninges in ovarian cancer is unclear. To date, there are no clinical guidelines for the management of this category of patients, and treatment of LMC in ovarian cancer is based on treatment protocols for meningeal carcinomatosis in other nosologies and on selected clinical observations presented in the world literature and personal experience. This article presents a clinical case of a patient with BRCA1-associated ovarian cancer and lesions of CNS meninges and parenchyma and our own experience in the treatment of this pathology. The treatment consisted of systemic anti-cancer therapy in combination with radiation therapy. Survival time after diagnosis of CNS metastases and treatment was 8 months. Key words: ovarian cancer, meningeal carcinomatosis, brain metastases, cytological examination, cerebrospinal fluid

Advanced strategies for nucleic acids and small-molecular drugs in combined anticancer therapy.

Cancer has been considered as complex malignant consequence of genetic mutations that control the cellular proliferation, differentiation and homeostasis, thus making tumor treatment extremely challenging. To date, a variety of cargo molecules, including nucleic acids drugs (pDNA, miRNA and siRNA), therapeutic drugs (doxorubicin, paclitaxel, daunomycin and gefitinib) and imaging agents (radioisotopes, fluorescence dyes, and MRI contrast agents) have been regarded as the potential medicines in clinical application. However, non-single therapeutic drug could induce the satisfied clinical results because of tumor heterogeneity and multiple drug resistance and the nanotechnology-based combined therapy is becoming an advanced important mode for enhanced anticancer effects. The review gathers the current advanced development to co-deliver small-molecular drugs and nucleic acids for the anticancer therapy with nanomedicine-based combination. Furthermore, the superiority is definitely presented and the barriers are detail discussed to surmount the clinical challenges. In final, future perspectives in rational direction for combined tumor therapy of drugs and nucleic acids are exhibited.

A heuristic algorithm solving the mutual-exclusivity-sorting problem.

Binary (or Boolean) matrices provide a common effective data representation adopted in several domains of computational biology, especially for investigating cancer and other human diseases. For instance, they are used to summarize genetic aberrations-copy number alterations or mutations-observed in cancer patient cohorts, effectively highlighting combinatorial relations among them. One of these is the tendency for two or more genes not to be co-mutated in the same sample or patient, i.e. a mutual-exclusivity trend. Exploiting this principle has allowed identifying new cancer driver protein-interaction networks and has been proposed to design effective combinatorial anti-cancer therapies rationally. Several tools exist to identify and statistically assess mutual-exclusive cancer-driver genomic events. However, these tools need to be equipped with robust/efficient methods to sort rows and columns of a binary matrix to visually highlight possible mutual-exclusivity trends. Here, we formalize the mutual-exclusivity-sorting problem and present MutExMatSorting: an R package implementing a computationally efficient algorithm able to sort rows and columns of a binary matrix to highlight mutual-exclusivity patterns. Particularly, our algorithm minimizes the extent of collective vertical overlap between consecutive non-zero entries across rows while maximizing the number of adjacent non-zero entries in the same row. Here, we demonstrate that existing tools for mutual-exclusivity analysis are suboptimal according to these criteria and are outperformed by MutExMatSorting. https://github.com/AleVin1995/MutExMatSorting. Supplementary data are available at Bioinformatics online.

The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.

PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression

MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), which is currently in several clinical trials for anti-cancer applications. However, MLN4924 also showed some off-target effects with potential to promote the growth of cancer cells which counteracts its anticancer activity. In this study, we found that MLN4924 increases the levels of PD-L1 mRNA and protein in dose- and time-dependent manners. Mechanistic study showed that this MLN4924 effect is largely independent of neddylation inactivation, but is due to activation of both ERK and JNK signals, leading to AP-1 activation, which is blocked by the small molecule inhibitors of MEK and JNK, respectively. Biologically, MLN4924 attenuates T cell killing in a co-culture model due to PD-L1 upregulation, which can be, at least in part, abrogated by either MEK inhibitor or anti-PD-L1 antibody. In an in vivo BALB/c mouse xenograft tumor model, while MLN4924 alone had no effect, combination with either MEK inhibitor or anti-PD-L1 antibody enhanced the suppression of tumor growth. Taken together, our study provides a sound rationale for effective anticancer therapy in combination of anti-PD-L1 antibody or MEK inhibitor with MLN4924 to overcome the side-effect of immunosuppression by MLN4924 via PD-L1 induction.

EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies.

Simple SummaryCisplatin is a chemotherapy drug widely used in the treatment of different cancer types. However, cisplatin displays a high range of toxicity and its use usually leads to resistance. Therefore, combination therapies that include cisplatin are explored to alleviate the problems that are elicited by cisplatin use. EZH2 is an epigenetic regulator with an increased expression and activity in many cancer types, which, in general, potentiates cancer growth and expansion. In the past decade, many EZH2 inhibitors were introduced and investigated for their anticancer properties. In this review paper, we explore the work that analyzed the joint action of EZH2 inhibitors and cisplatin in different tumor types. We found that combination therapy of EZH2 inhibitors and cisplatin could potentially be beneficial for the treatment of lung, ovarian, and breast cancers. However, in testicular germ cell tumors, according to the published data, such a combination could potentially have antagonistic effects.Anticancer monotherapies are often insufficient in eradicating cancer cells because cancers are driven by changes in numerous genes and pathways. Combination anticancer therapies which aim to target several cancer traits at once represent a substantial improvement in anticancer treatment. Cisplatin is a conventional chemotherapy agent widely used in the treatment of different cancer types. However, the shortcomings of cisplatin use include its toxicity and development of resistance. Therefore, from early on, combination therapies that include cisplatin were considered and used in a variety of cancers. EZH2, an epigenetic regulator, is frequently upregulated in cancers which, in general, potentiates cancer cell malignant behavior. In the past decade, numerous EZH2 inhibitors have been explored for their anticancer properties. In this overview, we present the studies that discuss the joint action of cisplatin and EZH2 inhibitors. According to the data presented, the use of cisplatin and EZH2 inhibitors may be beneficial in the treatment of lung, ovarian, and breast cancers, since there is a substantial amount of published evidence that suggests their concerted action. However, in testicular germ cell tumors, such a combination would not be recommended because cisplatin resistance seems to be associated with decreased expression of EZH2 in this tumor type.