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Abstract Background Non-small cell lung cancer (NSCLC) presents a significant challenge in the medical field due to its high incidence and resistance to chemotherapy. Chemoresistance in NSCLC diminishes treatment efficacy and contributes to poor patient outcomes. Matrine alkaloids have shown promise in reversing chemotherapy resistance in NSCLC by targeting DNA repair mechanisms. Methods Utilizing molecular dynamics simulations, we explored the interactions between Matrine alkaloids and DNA repair-related proteins to elucidate their impact on NSCLC cells. In vitro experiments involved treating A549/DDP cells with Matrine alkaloids to evaluate their sensitizing effects on lung cancer cells. Additionally, animal model experiments were conducted to validate the therapeutic potential of Matrine alkaloids in NSCLC treatment. Results Our findings demonstrate that Matrine alkaloids disrupt DNA damage repair processes in NSCLC cells, leading to increased sensitivity to chemotherapy. Molecular docking studies revealed the intricate mechanisms by which Matrine alkaloids interact with DNA repair proteins, impacting cell survival and proliferation. Both cell experiments and animal models confirmed the chemosensitizing effects of Matrine alkaloids in NSCLC treatment. Conclusion Matrine alkaloids offer a promising avenue for overcoming chemotherapy resistance in NSCLC by interfering with DNA repair pathways. This study lays a solid foundation for future clinical investigations into the potential of Matrine alkaloids as effective therapeutic agents for enhancing NSCLC treatment outcomes.

Background: Non-small cell lung cancer (NSCLC) presents a significant challenge in the medical field due to its high incidence and resistance to chemotherapy. Chemoresistance in NSCLC diminishes treatment efficacy and contributes to poor patient outcomes. Matrine alkaloids have shown promise in reversing chemotherapy resistance in NSCLC by targeting DNA repair mechanisms. Methods: Utilizing molecular dynamics simulations, we explored the interactions between Matrine alkaloids and DNA repair-related proteins to elucidate their impact on NSCLC cells. In vitro experiments involved treating A549/DDP cells with Matrine alkaloids to evaluate their sensitizing effects on lung cancer cells. Additionally, animal model experiments were conducted to validate the therapeutic potential of Matrine alkaloids in NSCLC treatment. Results: Our findings demonstrate that Matrine alkaloids disrupt DNA damage repair processes in NSCLC cells, leading to increased sensitivity to chemotherapy. Molecular docking studies revealed the intricate mechanisms by which Matrine alkaloids interact with DNA repair proteins, impacting cell survival and proliferation. Both cell experiments and animal models confirmed the chemosensitizing effects of Matrine alkaloids in NSCLC treatment. Conclusion: Matrine alkaloids offer a promising avenue for overcoming chemotherapy resistance in NSCLC by interfering with DNA repair pathways. This study lays a solid foundation for future clinical investigations into the potential of Matrine alkaloids as effective therapeutic agents for enhancing NSCLC treatment outcomes. [ABSTRACT FROM AUTHOR]

The abnormal metabolism of rapidly growing tumors can create an acidic tumor microenvironment (TME) that renders cancer cells resistant to chemotherapy and further facilitates endothelial-to-mesenchymal transition (EMT) progress to promote metastasis. Here, we developed a combination strategy consisting of (1) peritumorally injected scaffold that alleviates TME acidosis, and (2) intravenously injected nanoparticles that delivers anti-cancer agents to tumor. Concurrent treatment with these two drug delivery systems profoundly delayed the growth of primary tumor and reduced the spontaneous metastasis to lung in an orthotopic breast cancer mouse model. Mechanism studies both in vitro and in vivo further revealed that neutralization of TME pH by the hydrogel scaffold sensitized cancer cells to nanoparticle-based chemotherapy, thereby strengthening the cytotoxicity against tumor growth; In parallel, reversal of tumor acidity downregulated various pro-metastatic proteins intratumorally to block the EMT progress, thereby reducing the metastatic potential of cancer cells. This work provided proof-of-concept demonstration that chemotherapy sensitization and EMT suppression could be synchronized by the modulation of TME pH, which may be potentially beneficial for simultaneous inhibition of tumor growth and cancer metastasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) is a low-toxicity and high-efficiency anticancer treatment that can augment the cytotoxicity of doxorubicin (DOX) towards breast cancer cells, thereby exhibiting a favorable effect on chemotherapy sensitization., Objective: The study aimed to establish a hydrogel that sensitizes chemotherapy by inducing local inflammatory stimulation to change the tumor microenvironment and promote NO production. The purpose of the study was to examine the anti-tumor effect in vivo and in vitro., Methods: The functional properties of the composite hydrogels were tested by UV spectrophotometry and NO detection kit. CCK8, DCFH-DA fluorescent probe, Calcein-AM/PI detection kit, and confocal detection methods were used for the cytocompatibility and cytotoxicity of the composite hydrogels. The subcutaneous tumor volume, weight, and tumor inhibition rate of 4T1 breast cancer cells were evaluated for pharmacodynamic study in vivo., Results: Each component of hydrogel has good biocompatibility. The combination of gas therapy and chemotherapy can significantly enhance the effect of inhibiting tumor cell growth. The tumor growth of tumor- bearing mice in the hydrogel administration group was slow, and the tumor inhibition rate was 85.10%. The body weight grew steadily, and no significant pathological changes were observed in the H&E staining of major organs., Conclusion: A composite hydrogel with alginate as the carrier was successfully established, which was based on improving the tumor microenvironment to trigger gas therapy combined with chemotherapy for tumor treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.

Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus "synchronizing" the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy. Unlabelled Image • A dextran-deoxycholic acid amphiphilic polymer (Dex-DOCA) was successfully synthesized. • Paclitaxel and silibinin could be co-loaded into Dex-DOCA at a controlled synergistic ratio. • (PTX+SB) NP "synchronized" the in vivo biodistribution, transport and release of PTX and SB within tumor. • (PTX+SB) NP improved intratumoral penetration of drugs by regulating TME. • (PTX+SB) NP maximized therapeutic outcomes through chemotherapy sensitization and TME modulation. [ABSTRACT FROM AUTHOR]

Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and immunosuppressive tumor microenvironment (ITM). Herein, a LyP-1 and chondroitin sulfate (CS) dual-modified liposome co-loaded with paclitaxel (PTX) and cryptotanshinone (CTS), namely CS/LyP-1-PC Lip, is engineered for TNBC chemoimmunotherapy via induction of immunogenic cell death (ICD) and inhibition of signal transducer and activator of transcript-3 (STAT3) activation. CS/LyP-1-PC Lip enhances cellular uptake through p32 and CD44 dual receptor-mediated endocytosis. Within the tumor, the CS layer is continuously detached by hyaluronidase to release drugs. Subsequently, CTS sensitizes the cytotoxicity of PTX to 4T1 tumor cells. PTX induces ICD of tumor cells and facilitates infiltration of cytotoxic T lymphocyte to provoke immune response. Meanwhile, the concomitant delivery of CTS inhibits STAT3 activation to decrease infiltration of regulatory T cell, M2-type tumor-associated macrophage, and myeloid-derived suppressor cell, thus reversing ITM. Markedly, the dual-targeting liposome shows superior anti-tumor efficacy in subcutaneous TNBC mice and significant lung metastasis suppression in tumor metastasis model. Overall, this work offers a feasible combination regimen and a promising nanoplatform for the development of TNBC chemoimmunotherapy., (© 2023 Wiley-VCH GmbH.)

Purpose: Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells. Methods: Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho- Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay. Results: TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU. Conclusion: TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells. [ABSTRACT FROM AUTHOR]

Checkpoint kinase 1 (Chki) is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chki expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chki inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chki is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.

Pancreatic cancer is a malignant disease without efficient treatment. Improved treatments are urgently needed to enhance or replace chemotherapy. Here we used a small molecular compound LB-100 to assess the effect of pharmacological inhibition of protein phosphatase 2A (PP2A) in combination with doxorubicin on the proliferation of pancreatic cancer in cell lines and a xenograft model. LB-100 moderately reduced PP2A activity and the growth of the cell lines but did not show chemosensitization in vitro. In vivo , however, LB-100 synergistically enhanced the activity of doxorubicin. This effect was associated with increased microvessel density, blood perfusion, and doxorubicin concentrations within the xenografts. Mechanically, LB-100 induced expression of hypoxia-induced factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). In an umbilical vein endothelial cell monolayer model for measuring changes in vascular permeability, increased VEGF secretion following exposure to LB-100 and doxorubicin was accompanied by increased amounts of doxorubicin penetrating the endothelial barrier. In conclusion, PP2A inhibition by LB-100 enhanced the cytotoxicity of doxorubicin in vivo but not in vitro potentially via HIF-1α-VEGF mediated angiogenesis. Combining inhibition of PP2A with chemotherapeutic regimens may enhance their effectiveness against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Abstract: Docosahexaenoic acid (DHA, a lipid of marine origin) has been found to enhance the activity of several anticancer drugs through an oxidative mechanism. To examine the relation between chemosensitization by DHA and tumor cells antioxidant status, we used two breast cancer cell lines: MDA-MB-231, in which DHA increases sensitivity to doxorubicin, and MCF-7, which does not respond to DHA. Under these conditions, reactive oxygen species (ROS) level increased on anthracycline treatment only in MDA-MB-231. This was concomitant with a decreased cytosolic glutathione peroxidase (GPx1) activity, a crucial enzyme for protection against hydrogen and lipid peroxides, while major antioxidant enzyme activities increased in both cell lines in response to ROS. GPx-decreased activity was accompanied by an accumulation of glutathione, the GPx cosubstrate, and resulted from a decreased amount of GPx protein. In rat mammary tumors, when a DHA dietary supplementation led to an increased tumor sensitivity to anthracyclines, GPx1 activity was similarly decreased. Furthermore, vitamin E abolished both DHA effects on chemotherapy efficacy enhancement and on GPx1 inhibition. Thus, loss of GPx response to an oxidative stress in transformed cells may account for the ability of peroxidizable targets such as DHA to enhance tumor sensitivity to ROS-generating anticancer drugs. [Copyright &y& Elsevier]

Soft tissue sarcomas are a histologically heterogeneous group of rare mesenchymal cancers for which treatment options leading to increased overall survival have not improved in over two decades. The current study shows that pharmacological ascorbate (systemic high dose vitamin C achieving ≥ 20mM plasma levels) is a potentially efficacious and easily integrable addition to current standard of care treatment strategies in preclinical models of fibrosarcoma and liposarcoma both in vitro and in vivo. Furthermore, enhanced ascorbate-mediated toxicity and DNA damage in these sarcoma models were found to be dependent upon H 2 O 2 and intracellular labile iron. Together, these data support the hypothesis that pharmacological ascorbate may represent an easily implementable and non-toxic addition to conventional sarcoma therapies based on taking advantage of fundamental differences in cancer cell oxidative metabolism., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)