Synergistic Anticancer Efficacy Research Articles

Concurrent inhibition of IR, ITGB1, and CD36 perturbated the interconnected network of energy metabolism and epithelial-to-mesenchymal transition in breast cancer cells.

Altered energy metabolism is an emerging hallmark of cancer and plays a pivotal in cell survival, proliferation, and biosynthesis. In a rapidly proliferating cancer, energy metabolism acts in synergism with epithelial-to-mesenchymal transition (EMT), enabling cancer stemness, dissemination, and metastasis. In this study, an interconnected functional network governing energy metabolism and EMT signaling pathways was targeted through the concurrent inhibition of IR, ITGB1, and CD36 activity. A novel multicomponent MD simulation approach was employed to portray the simultaneous inhibition of IR, ITGB1, and CD36 by a 2:1 combination of Pimozide and Ponatinib. Further, in-vitro studies revealed the synergistic anticancer efficacy of drugs against monolayer as well as tumor spheroids of breast cancer cell lines (MCF-7 and MDA-MB-231). In addition, the combination therapy exerted approximately 40% of the apoptotic population and more than 1.5- to 3-fold reduction in the expression of ITGB1, IR, p-IR, IRS-1, and p-AKT in MCF-7 and MDA-MB-231 cell lines. Moreover, the reduction in fatty acid uptake, lipid droplet accumulation, cancer stemness, and migration properties were also observed. Thus, targeting IR, ITGB1, and CD36 in the interconnected network with the combination of Pimozide and Ponatinib represents a promising therapeutic approach for breast cancer.

Co‐encapsulation of Curcumin and Paclitaxel using Non‐ionic Surfactant Based Nanovesicles Suppresses Growth of Ovarian Carcinoma through the Inhibition of Nuclear Factor κB and AKT1

AbstractCurcumin (Cur) indicates P‐glycoprotein inhibitory activity by downregulating the nuclear factor (NF)‐κB signaling and the PI3K/AKT/mTOR pathway. Curcumin has limited due to its low water‐solubility. Therefore, using novel chemotherapeutic nanoformulations of curcumin or combining it with paclitaxel (PCL) may be more effective against cancer. Recently, we demonstrated that the combination of chemotherapy with PCL and Cur, using non‐ionic surfactant‐based nano‐vesicles (NISV), exhibited enhanced synergistic anticancer efficacy in breast cancer cells. However, the effect of combining these drugs using non‐ionic surfactant‐based nano‐vesicles for treating ovarian cancer, particularly in terms of their influence on AKT1 and NF‐kappa B, has not been investigated. Hereupon, we decided to investigate the single and combination treatment with Cur and PCL on cell apoptosis, expression of the AKT‐1 gene, and determination of p65‐NF‐κB in OVCAR‐3 cell. The combination of chemotherapy with curcumin and paclitaxel, using NISV, resulted in a higher rate of apoptosis, more efficient reduction in AKT‐1 gene expression (91.2 % reduction in PCL‐NISV+Cur‐NISV vs. 72.89 % reduction in PCL+Cur free solution), and 79.42 % reduction in NF‐κB activity compared to individual treatments. The findings indicate that combining curcumin and paclitaxel using non‐ionic surfactant‐based nano‐vesicles may be a promising strategy for reducing ovarian cancer growth.

Apoptosis-driven synergistic anti-cancer efficacy of ethyl acetate extract of Memecylon sisparense Gamble leaves and doxorubicin in in-vitro and in-vivo models of triple-negative breast cancer

In the spectrum of breast neoplasms, approximately 15 to 20% of all diagnosed cases are triple-negative breast carcinoma. TNBC grows and spreads faster than other invasive breast cancers and has a worse prognosis. The existing therapies and chemotherapeutic drugs have several limitations, so the development of safe and affordable treatment options is currently in demand. Hence, this research focuses on scientifically evaluating the therapeutic anticancer effect of ethyl acetate extract of MSG and its combined efficacy with doxorubicin against TNBC. MSG has shown an IC50 value of 48.40±1.68µg/ml on the MDA-MB-231 cell line, and the combination of MSG with Dox demonstrated the synergistic effect. Apoptotic changes such as membrane blebbing chromatin condensation were observed in MSG alone and in combination with doxorubicin treatments. Apoptosis was confirmed with Annexin V-FITC/PI staining and increased apoptotic markers such as Cleaved caspase-3 Bax and decreased anti-apoptotic markers Bcl-2 by western blotting. The tumor burden significantly decreased in MSG and combination treatment groups while restoring their body weights. Meanwhile, the Dox-treated group indicated a decreased tumor burden combined with weight loss. The present investigation revealed that MSG and doxorubicin have a synergistic anticancer effect in TNBC.

Recent Progress in the Hesperetin Delivery Regimes: Significance of Pleiotropic Actions and Synergistic Anticancer Efficacy.

In the plant kingdom, flavonoids are widely distributed with multifunctional immunomodulatory actions. Hesperetin (HST) remains one of the well-studied compounds in this domain, initially perceived in citrus plants as an aglycone derivative of hesperidin (HDN). Natural origin, low in vivo toxicity, and pleiotropic functional essence are the foremost fascinations for HST use as an anticancer drug. However, low aqueous solubility accompanied with a prompt degradation by intestinal and hepatocellular enzymes impairs HST physiological absorption. Remedies attempted herein comprise the synthesis of derivatives and nanocarrier (NC)-mediated delivery. As the derivative synthesis aggravates the structural complexity, NC-driven HST delivery has emerged as a sustainable approach for its sustained release. Recent interest in HST has been due to its significant anticancer potential, characterized via inhibited cell division (proliferation), new blood vessel formation (angiogenesis), forceful occupation of neighboring cell's space (invasion), migration to erstwhile physiological locations (metastasis) and apoptotic induction. The sensitization of chemotherapeutic drugs (CDs) by HST is driven via stoichiometrically regulated synergistic actions. Purpose and Conclusion: This article sheds light on HST structure-function correlation and pleiotropic anticancer mechanisms, in unaided and NC-administered delivery in singular and with CDs synergy. The discussion could streamline the HST usefulness and long-term anticancer efficacy.

ATP-responsive and functionalized framework nucleic acid for synergistic radio-immunotherapy

Traditional radiotherapy is ineffective against some aggressive and recurrent tumors. In clinical therapy, low-dose radiations are frequently utilized to lessen the negative effects of X-rays. There is an urgent need to develop a novel therapeutic strategy for adjuvant radiotherapy. An ATP-responsive and functionalized framework nucleic acid delivery system (Op-TGA) was developed using local irradiation, which can cause enormous ATP release from tumors. The framework nucleic acid carrying the nucleic acid fragment of immune adjuvant and antigen peptides can be massively aggregated and successfully released in a high-concentration ATP environment using this delivery platform. Thus, intravenous injection of Op-TGA into tumor-bearing mice after radiation can precisely concentrate around the tumor tissue, and once released, it is rapidly taken up by antigen-presenting cells, stimulating the cellular immune response. The conjunction of radiotherapy and Op-TGA has a significant synergistic anticancer efficacy and establishes an immunological memory effect to prevent tumor recurrence. Op-TGA developed here offers a new technique for Radio-immunotherapy that is closely related to clinical therapy and has great clinical application potential.

An Insight on Synergistic Anti-cancer Efficacy of Biochanin A and Sulforaphane Combination Against Breast Cancer.

Breast cancer is a serious malignancy that has higher rate of morbidity and mortality. It has been known to affect the women indifferently. The lack and side effects in the current therapeutic modules result in the search of the wide treatment options including combinatorial treatment. The goal of this study was to investigate combinatorial anti-proliferative efficacy of biochanin A (BCA) and sulforaphane (SFN) against MCF-7 breast cancer cells.The study involves the utilisation of various qualitative techniques including cytotoxicity analysis (MTT), morphogenic analysis, AO/EtBr, DAPI, ROS, cell cycle, and cell migration analysis in order to examine the combinatorial efficacy of BCA and SFN in inducing the cell death.The results had shown that the cytotoxicity of BCA and SFN was found to be around 24.5 µM and 27.2 µM respectively, while the combination of BCA and SFN had shown an inhibitory activity at about 20.1 µM. And furthermore, AO/EtBr and DAPI had shown a profound increase in apoptogenic activity of compounds when treated in combination at lower dose. This apoptogenic activity may be attributed to the increased ROS production. Moreover, it has been shown that the BCA and SFN have been involved in the down-regulation of ERK-1/2 signalling pathway resulting in induction of apoptosis of cancer cells.Thus, our results had concluded that BCA and SFN co-treatment could be used as an efficient therapeutic target against breast cancer. Furthermore, in vivo efficiency by which the co-treatment induces apoptosis has to be deliberated further in near future to make their use commercially.

Cascade-amplified self-immolative polymeric prodrug for cancer therapy by disrupting redox homeostasis.

The amplification of reactive oxygen species (ROS) generation and glutathione (GSH) depletion in cancer cells represents a promising strategy to disrupt redox homeostasis for cancer therapy. Quinone methide and its analogs (QM) have recently been recognized as potential GSH scavengers for anticancer applications; however, an effective QM prodrug is yet to be developed. In this study, we prepare a self-immolative polymeric prodrug (SPP), which could be selectively degraded to generate large quantities of QMs in cancer cells during the spontaneous stepwise head-to-tail degradation of SPP. The amphiphilic SPP is self-assembled into nano-sized micelles, allowing for encapsulating 2-methoxy-β-estradiol (2ME), an anticancer drug that produces a large amount of intracellular ROS. When SPP@2ME, as the cascade-amplified prodrug, is treated on the cancer cells, 2ME is rapidly released at the ROS-rich intracellular environment by degradation of SPP, thus generating more ROS that triggers the degradation of more SPP chains. Such a domino-like cascade-amplified feedback loop significantly amplifies oxidative stress and disrupts the redox homeostasis in cancer cells. This unique strategy provides synergistic anticancer therapeutic efficacy and demonstrates an important perception in innovative and precise nanomedicine.

Photoallosteric Polymersomes toward On‐Demand Drug Delivery and Multimodal Cancer Immunotherapy (Adv. Mater. 24/2023)

Cancer Immunotherapy In article number 2210986, Mingming Ding and co-workers construct a photoallosteric polymersome (PAP) that undergoes a rapid conformational transition from β-sheet to α-helix upon exposure to near-infrared light irradiation. Photoinduced allosteric behavior specifically enhances cell penetration and lysosome escape and reconstructs the vesicular membrane structure for on-demand release of hydrophilic and hydrophobic drugs, thus remolding the immune microenvironment and achieving excellent synergistic anticancer efficacy in vivo without tumor recurrence and metastasis.

Abstract 3821: Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic cancer is one of the most devastating malignancies due to the development of intrinsic chemoresistance following chemotherapy. Extracellular matrix (ECM) proteins are intimately linked to cellular proliferation, invasion, and acquisition of chemoresistance in PDAC cells, making them promising therapeutic targets in this malignancy. Naturally occurring dietary botanicals, including berberine (BER) and emodin (EMO), have been shown to suppress ECM as one of the mechanism(s) for their anti-tumorigenic activity, along with their time-tested safety and cost-effectiveness. In addition, both BER and EMO are also known to induce apoptosis by modulating different pathways and regulating pro-apoptotic genes. Herein, we hypothesized that combined treatment with BER and EMO might exhibit synergistic anticancer efficacy by targeting the ECM and apoptotic pathways in PDAC cells. Methods: We undertook genomewide transcriptomic profiling analysis to identify critical ECM-related genes differentially expressed in PDAC. Subsequently, the TCGA dataset was analyzed to identify the prognostic significance of ECM-associated genes with overall survival (OS) and disease-free survival (DFS) in PDAC. A series of cell culture experiments were performed using PDAC cells, followed by their validation in patient-derived organoids to examine the synergistic anti-proliferative and chemopreventive effects of BER and EMO against PDAC. Results: Transcriptomic profiling identified that LAMB3 expression was significantly upregulated in PDAC tissue (P < 0.01) and was significantly associated with poor OS and DFS in PDAC patients (P < 0.01). The combination of BER and EMO displayed superior synergistic anti-tumor potential in PDAC cells vs. individual compounds, as revealed by cell proliferation, clonogenicity, migration, and invasion assays. The combination of BER and EMO also altered the expression of key proteins involved in cellular apoptosis, epithelial-mesenchymal-transition, and EGFR/ERK//AKT growth factor signaling pathways. Finally, these findings were successfully validated in PDAC patient-derived 3D organoids. Conclusions: We provide the first evidence that combined treatment with berberine and emodin exerts synergistic anti-cancer activity in PDAC, primarily regulated through the LAMB3-mediated interaction with other members of the EGFR-signaling pathway. Citation Format: CAIMING XU, SILEI SUI, Keisuke Okuno, Silvia Pascual-Sabater, Cristina Fillat, Ajay Goel. Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3821.

Photoallosteric Polymersomes toward On-Demand Drug Delivery and Multimodal Cancer Immunotherapy.

Allosteric transitions can modulate the self-assembly and biological function of proteins. It remains, however, tremendously challenging to design synthetic allosteric polymeric assemblies with spatiotemporally switchable hierarchical structures and functionalities. Here, a photoallosteric polymersome is constructed that undergoes a rapid conformational transition from β-sheet to α-helix upon exposure to near-infrared light irradiation. In addition to improving nanoparticle cell penetration and lysosome escape, photoinduced allosteric behavior reconstructs the vesicular membrane structure, which stimulates the release of hydrophilic cytolytic peptide melittin and hydrophobic kinase inhibitor sorafenib. Combining on-demand delivery of multiple therapeutics with phototherapy results in apoptosis and immunogenic death of tumor cells, remold the immune microenvironment and achieve an excellent synergistic anticancer efficacy in vivo without tumor recurrence and metastasis. Such a light-modulated allosteric transition in non-photosensitive polymers provides new insight into the development of smart nanomaterials for biosensing and drug delivery applications.

Acidity-Biodegradable Iridium-Coordinated Nanosheets for Amplified Ferroptotic Cell Death Through Multiple Regulatory Pathways.

Ferroptosis-based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid-biodegradable iridium-coordinated nanosheets (Ir-Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir-Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir-Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO-1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir-Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir-Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment.

Zinc Acts Synergistically with Berberine for Enhancing Its Efficacy as an Anti-cancer Agent by Inducing Clusterin-Dependent Apoptosis in HT-29 Colorectal Cancer Cells.

It is now widely accepted that anti-cancer medications are most effective when administered in combination. Zinc is an essential micronutrient whilst berberine is a well-known natural phytochemical, both having multiple molecular mechanisms of action. The present study aimed to determine the combinatorial effect of zinc and berberine on the human adenocarcinoma HT-29 cancer cell line. The anti-proliferative activity of berberine and zinc was determined by cell viability and colony-forming assays. The combination index and drug reduction index values of zinc and berberine co-treatments were estimated by suitable software. Flow cytometry was used to analyse cell cycle distribution and Annexin V/PI staining. The expression of apoptosis and zinc signalling markers were analysed by RT-qPCR and immunoblot analysis. Berberine decreased the viability of colon cancer cells in a dose-dependent manner whilst zinc alone had no significant influence on it. However, zinc and berberine co-treatment resulted in a synergistic anti-cancer action which was demonstrated by G2/M phase arrest of cell growth at a lower dose of berberine. Annexin V assay demonstrated that the synergistic impact of zinc and berberine boosted the number of apoptotic cells. Gene expression analysis at both transcriptional and translational levels showed the upregulation of apoptotic (caspase-3 and caspase-8) and a zinc-sensing receptor (GPR39) gene with concomitant downregulation of anti-apoptotic genes like proliferating cell nuclear antigen (PCNA) and clusterin. Our findings showed that the combination of zinc and berberine has synergistic anti-cancer efficacy and thus could be used as a potential chemopreventive option for colon cancer.

MiRNA-16-1 Suppresses Mcl-1 and Bcl-2 and Sensitizes Chronic Lymphocytic Leukemia Cells to BH3 Mimetic ABT-199.

ObjectiveChronic lymphoid leukemia (CLL) is the most common type of leukemia among adults. Increased levels of Mcl-1 and Bcl-xL is linked to resistance to Bcl-2 inhibitors including ABT-199. In this study, we investigated the effect of miRNA-16-1 on apoptosis and sensitivity of the CLL cells to ABT-199. Materials and Methods In this experimental study, the Mcl-1 and Bcl-2 expression were measured using qualitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The effect of treatments on cell survival and growth were explored with MTT assay and Trypan blue assay, respectively. The drug interaction was evaluated using combination index analysis. Apoptosis was assessed by ELISA cell death and caspase-3 activity assays. Results MiRNA-16-1 markedly inhibited the expression of Mcl-1 and Bcl-2 in a time dependent manner (P<0.05, relative to blank control). Pretreatment with miRNA-16-1 synergistically suppressed the cell growth and survival and reduced the half-maximal inhibitory concentration (IC50) value of ABT-199. Moreover, miRNA-16-1 markedly augmented the apoptotic effect of ABT-199 in CLL cells (P<0.05). ConclusionOur findings propose that miRNA-16-1 act in concert with ABT-199 to exert synergistic anticancer efficacy against CLL, which is attributed to the inhibition of Bcl-2 and Mcl-1. This may propose a promising strategy for CLL resistant patients.

Activatable self-assembled organic nanotheranostics: Aspartyl aminopeptidase triggered NIR fluorescence imaging-guided photothermal/photodynamic synergistic therapy

Phototherapy has developed as a powerful method for remedial modalities. The conventional photosensitizers are “always on” state and lack tumor targeting, which contributed to poor therapeutic effect and high toxicity. Therefore, we developed an aspartyl aminopeptidase (DNPEP) activated self-assembled organic nanoparticles (NRh-Asp NPs) with sensitive external irradiation-induced photothermal therapy and photodynamic therapy (PTT/PDT). NRh-Asp NPs can be activated to NRh–NH2 NPs by DNPEP, demonstrating strong near-infrared (NIR) fluorescence, and efficiently generating heat and singlet oxygen under the near-infrared laser. NRh-Asp NPs was successfully used for visualizing DNPEP in vitro and in vivo in NIR region, and demonstrated good synergistic anti-cancer efficacy of PDT and PTT. These results suggest that DNPEP-mediated NRh-Asp NPs are promising candidates for image-guided phototherapeutic of tumor.

Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid–functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

Co-assemblies based on natural Hemslecin A and β-sitosterol as a new sight for synergistic anti-gastric cancer efficacy in TCM

The curative effect of traditional Chinese medicine (TCM) is definite, but the material basis of TCM is not clear enough, or some known natural small molecules (NSMs) perform favorable pharmacological activities, however, the functioning modes of therapeutic effect need to be further elucidated. Here, we first report the co-assembly properties of tetracyclic triterpenoids and steroid derived from Chinese herb Hemsleya penxianensis. The changes of morphology, properties and driving force as well as the mechanism of co-assembly are explored by chemical characterization and computer simulation. Furthermore, the co-assembled drugs exhibit a remarkably enhanced, synergistic anticancer efficacy. The reasons could be that morphology and hydrophilicity are improved after their interaction, thus making co-assembly adhere to the cells more easily to exert its effects. This research not only expands the potential application of natural products, but also provides the new sight of TCM (H. penxianensis) in therapeutic effect with their inner substance co-assemblies.

Discovery of novel 7,8-dihydropteridine-6(5H)-one-based DNA-PK inhibitors as potential anticancer agents via scaffold hopping strategy

DNA-dependent protein kinase (DNA-PK) is an essential element in the DNA damage response (DDR) pathway and has been regarded as a druggable target for antineoplastic agents. Starting from AZD-7648, a potent DNA-PK inhibitor being investigated in phase II clinical trials for advanced cancer treatment, two series of DNA-PK inhibitors were rationally designed via scaffold hopping strategy, synthesized, and assessed for their biological activity. Most compounds exhibited potent biochemical activity on DNA-PK enzymatic assay with IC50 values below 300 nM. Among these compounds, DK1 showed the best DNA-PK-inhibitory potency (IC50 = 0.8 nM), slightly better than that of AZD-7648 (IC50 = 1.58 nM). Mode of action studies revealed that compound DK1 decreased the expression levels of γH2A.X and demonstrated synergistic antiproliferative activity against a series of cancer cell lines when used in combination with doxorubicin. Moreover, DK1 showed reasonable in vitro drug-like properties and favorable in vivo pharmacokinetics as an oral drug candidate. Importantly, the combination therapy of DK1 with DNA double-strand break (DSB)-inducing agent doxorubicin showed synergistic anticancer efficacy in the HL-60 xenograft model with a tumor growth inhibition (TGI) of 52.4% and 62.4% for tumor weight and tumor volume, respectively. In conclusion, DK1 is a novel DNA-PK inhibitor with great promise for further study.

Inhibition of Stearoyl-CoA Desaturase 1 Potentiates Anti-tumor Activity of Amodiaquine in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death with few therapeutic treatment options. Under adverse tumor microenvironment, autophagy is an important mechanism of metabolic adaptations to sustain the survival and proliferation of tumor cells. Therefore, targeting autophagic activity represents a promising opportunity for NSCLC treatment. Here, we found that amodiaquine (AQ) increased autophagosome numbers and LC3BII and p62 at protein levels in A549 lung cancer cells suggesting the blockade of autophagic flux by AQ. To identify the key metabolic vulnerability associated with autophagy inhibition by AQ treatment, we then performed transcriptomics analysis in the presence or absence of AQ in A549 lung cancer cells and found stearoyl-CoA desaturase 1 (SCD1) was one of the most highly upregulated with AQ exposure. The induction of SCD1 by AQ exposure at both protein and mRNA level suggests that SCD1 could represent a potential therapeutic target of AQ treatment. Treatment of AQ in combination with SCD1 inhibition by A939572 demonstrated robust synergistic anti-cancer efficacy in cell proliferation assay and a lung cancer mouse xenograft model. Taken together, our study identified SCD1 could be a new therapeutic target upon autophagy inhibition by AQ exposure. Combinational treatment of autophagy inhibition and SCD1 inhibition achieves synergistic anti-tumor effect both in vitro and in vivo. This combinational approach could be a promising strategy for NSCLC treatment.

Ratiometric co-delivery of hydroxychloroquine and calculated low-dose paclitaxel efficiently suppresses tumor growth in hepatocellular carcinoma mouse models in vivo

Utilizing a liposomal nanocarrier to co-encapsulate autophagy inhibitor hydroxychloroquine (HCQ) plus a calculated low-dose chemotherapeutic agent paclitaxel (PTX), we demonstrated a ratiometrically designed nanoformulation with synergistic anti-cancer efficacy in various hepatocellular carcinoma (HCC) mouse models. Using CompuSyn software to calculate drug synergy, we determined the synergistic drug ratios in cultured HCC cells, which became the reference to design ratiometric liposomes. Particle synthesis was accomplished by a film dispersion method for the calculated amount of PTX lipid incorporation and a remote loading process for HCQ import using ammonium sulfate. Ratiometric co-delivery led to synergistic killing effect and autophagy inhibition in cultured HCC cells and nude mice that were used to grow subcutaneous human HepG2 xenografts. Intravenous injection of ratiometric liposome yielded the most effective tumor shrinkage compared to various controls, including the free drug mix. A similar outcome was achieved in a HepG2 orthotopic model. We further explored the anti-cancer effect in a Hep1–6 murine HCC in immunocompetent mice, with or without co-administrated anti-PD1 antibody. Anti-PD1 antibody synergized with HCQ/PTX ratiometric liposome in the immunocompetent model.

Self-Rectifiable and Hypoxia-Assisted Chemo-Photodynamic Nanoinhibitor for Synergistic Cancer Therapy.

Photodynamic therapy (PDT) can eradicate cancer cells under light irradiation, mainly because of reactive singlet oxygen (1O2) being transformed from intratumoral oxygen. Nonetheless, the consumption of oxygen during PDT results in serious hypoxic conditions and an elevated hypoxia-inducing factor-1α (HIF-1α) level that hamper further photodynamic efficacy and induce tumor metastasis. To address this problem, we developed hypoxia-assisted NP-co-encapsulating Ce6 (photosensitizer) and YC-1 (HIF-1α inhibitor) as a self-rectifiable nanoinhibitor for synergistic antitumor treatment. PDT-aggravated intracellular hypoxic stress facilitated NP dissociation to release the drug (YC-1), which achieved tumor killing and HIF-1α inhibition to further enhance the therapeutic effect of PDT and prevent tumor metastasis. Besides, in vivo studies revealed that the HC/PI@YC-1 NPs afforded synergistic anticancer efficacy with minimal toxicity. Therefore, this study provides a prospective approach against PDT drawbacks and combination cancer therapy.