Tumor Cell Toxicity Research Articles

Protein Immobilization Inspired Lysosomal Disruption for Efficient Nuclear Drug Delivery.

The high metabolism and excessive growth of tumor cells result in the development of a tumor microenvironment (TME) and enhanced lysosomal activity within the cells, which can eliminate chemotherapeutics. Consequently, the design of nanocarriers that respond to TME and target tumor cell lysosomes represents an optimal strategy to enhance drug specificity and utilization efficiency. Herein, inspired by protein immobilization, a dual-responsive supramolecular nanomedicine FPA/DOX is developed for specifically targeting the TME and tumor cell lysosomes. Upon hypoxia and acidic response, FPA/DOX exposes benzaldehyde groups that engage with amino groups on lysosomal proteins by protein covalent immobilization reaction─an imidization condensation reaction, leading to protein denaturation and inactivation and inducing lysosomal membrane permeabilization (LMP). This LMP process not only triggers lysosomal-dependent cell death (LDCD) but also facilitates the rapid translocation of released DOX into the cell nucleus. In vitro experiments have demonstrated that the tumor cell toxicity of FPA/DOX is 4.2 times that of free DOX. Additionally, in vivo studies have verified the high biosafety of FPA/DOX, with a remarkable tumor inhibition rate of 95.27%. In summary, the lysosomal disruption inspired by protein immobilization has pioneered an approach for tumor treatment and holds great potential in biomedical applications.

Engineering a Near-Infrared D-A-A-D BODIPY Dimer for ROS Generation and Photothermal Conversion in Multimodal Synergistic Phototherapy.

To address the limitations of traditional single-mode phototherapy, this study developed a novel, symmetrical D-A-A-D structured BODIPY dimer (P-P) via a facile "one-pot" oxidative homocoupling reaction, with triphenylamine as the electron donor (D), BODIPY as the electron acceptor (A), and butadiyne as the conjugated bridge. Compared to its D-A monomer counterpart (P), P-P displayed a red-shifted absorption spectrum (465-725 nm), enhanced charge separation, an extended triplet excited-state lifetime (165 μs vs 104 μs), and significantly improved type I, type II, and total reactive oxygen species (ROS) generation, along with superior photothermal conversion efficiency. These properties enable P-P to achieve multimodal phototherapy with enhanced therapeutic efficacy. As a result, P-P demonstrated efficient cellular uptake, high phototoxicity (with an IC50 of 15.2 μM), and minimal dark toxicity in tumor cells. This work offers a promising strategy for developing high-performance phototherapeutic agents, paving the way for advancing multimodal synergistic phototherapy in clinical applications.

SPIONs: Paving the Way for Targeted Drug Delivery to Cancer Cells

Abstract: Superparamagnetic iron oxide nanoparticles have gained considerable attention in drug delivery due to their superparamagnetic characteristics. SPIONs have a greater surface-to-volume ratio, size, superficial chemistry, and superparamagnetic characteristics, which allow them to be covered by external magnetic fields. These properties make SPIONs promising nanoparticles for drug delivery systems. A great advantage of the superparamagnetic characteristics is magnetic properties. SPIONs are magnetic and thoroughly demagnetized when the field of the electromagnet is pulled out. These characteristics permit their targeted delivery to a particular tissue or cell following a magnetic field. Furthermore, SPIONs can be fabricated with particular ligands, such as peptides or antibodies, to increase their efficiency in desired cells or tissues. This permits delivery, particularly to the desired cell type, increases therapeutic activity, and reduces off-target effects. Moreover, SPIONs exhibit imaging characteristics. However, this review highlights the capabilities of SPIONs for targeted drug delivery to reduce tumor cell toxicity.

A comprehensive assessment of the antiproliferative effects of Cymbopogon winterianus essential oil, citronellal, and citronellal complexed with β-cyclodextrin on cervical cancer cell line (HeLa)

A comprehensive assessment of the antiproliferative effects of Cymbopogon winterianus essential oil, citronellal, and citronellal complexed with β-cyclodextrin on cervical cancer cell line (HeLa)

Anti-lung cancer synergy of low-dose doxorubicin and PD-L1 blocker co-delivered via mild photothermia-responsive black phosphorus.

We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40°C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy.

Abstract 3305: Golcadomide (CC-99282) is a novel CELMoD® agent with antiproliferative activity and combinatorial potential in disease models of chronic lymphocytic leukemia

Abstract Chronic Lymphocytic Leukemia (CLL) is an adult leukemia characterized by the accumulation of incompetent B lymphocytes expressing CD19, CD20, CD23, and CD5. Current therapies include chemotherapy and combination with targeted therapies such as ibrutinib (Bruton’s tyrosine kinase inhibitor), venetoclax (BCL2 inhibitor), and obinutuzumab (anti-CD20). The tumor microenvironment promotes CLL development and drug resistance. Golcadomide (GOLCA, CC-99282) is an oral cereblon E3 ligase modulator (CELMoD®) agent with immunomodulatory and tumor cell-autonomous activities under clinical investigation for R/R non-Hodgkin lymphomas and CLL/SLL. Here we investigated the effect of GOLCA on inhibiting proliferation and inducing apoptosis of CLL preclinical models by degrading Ikaros and Aiolos. We also studied its combination with other anti-CLL agents. A panel of 10 CLL cell lines and 15 primary CLL patient samples were used to assess efficacy of GOLCA alone or in combination with ibrutinib (Ibru), venetoclax (Ven), and obinutuzumab (Obi). Primary CLL cells were grown ex vivo in a co-culture system with CD40L expressing fibroblasts designed to mimic the CLL lymph node microenvironment. Substrate degradation, viability, cell cycle and immunophenotyping were assessed by flow cytometry. GOLCA showed potent in vitro antiproliferative activity on 6 out of 10 CLL cell lines, including those with high-risk features, with IC50 of 1-20 nM. It also inhibited CLL stimulated cell proliferation and induced apoptosis in all evaluated patient samples in the co-culture system, with low to sub-nanomolar IC50, independent of IGHV mutation status and other chromosomal characteristics. Cell-cycle analysis confirmed inhibition of proliferation in the 5 patient samples evaluated after 3 days of treatment with GOLCA, with a dose-dependent decrease in the fraction of cells in the S phase. GOLCA also demonstrated degradation of the proximal substrates Ikaros and Aiolos in tumor and T cells from CLL patient samples. In combination with Obi, Ven, and Ibru, GOLCA led to synergistic or additive tumor cell toxicity in most patient samples evaluated, suggesting potential clinical benefit of these targeted agent combinations. Additive tumor toxicity was observed in two out of four patient samples when GOLCA was combined with Ibru. We have previously demonstrated that GOLCA induces immune activation in T cells from healthy donor PBMCs. In co-cultures of CLL PBMCs and CD40L-expressing fibroblasts, GOLCA increased T cell numbers and activation characteristics. Ven inhibited this immune activation, while Obi or Ibru maintained the immune activation. Collectively, these findings suggest that GOLCA, alone or in combination with targeted agents, may produce clinical benefit in CLL patients. Citation Format: Antonia Lopez-Girona, Maria Dolores Jimenez-Nunez, Diego Sobradillo, Soraya Carrancio, Preethi Janardhanan, Gauri Deb, Lynda Groocock, Daniel Pierce, Neil Bence, Mark Rolfe. Golcadomide (CC-99282) is a novel CELMoD® agent with antiproliferative activity and combinatorial potential in disease models of chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3305.

Design of a Nanodelivery System with High Loading Efficiency by Improving π‐π Interactions with Drugs

Abstractπ‐π interactions, serving as a pivotal driving force, hold enduring significance in the realm of drug delivery system development, primarily due to the prevalence of aromatic moieties in a substantial number of clinically relevant pharmaceutical compounds. Herein, we constructed a novel carbon nitride compound called PTCNx, featuring a large π‐conjugated skeleton, and employed it as a carrier for delivering aromatic clinical drugs for the first time. We conducted sequence characterization of their chemical structure, optical properties, and morphology, along with extensive research to analyze their significant enhancement in drug loading capacity. Of particular note was the exceptional loading efficiency of Doxorubicin (DOX) under alkaline conditions, achieving an unexpected 99 % efficacy, significantly surpassing the capabilities of traditional carbon nitrides with limited π‐conjugated systems. Cell tests illustrated that PTCN550 carrier exhibited favorable biocompatibility and low toxicity for normal and tumor cells, showing its potential as a drug carrier. However, PTCN550‐DOX complex effectively inhibited both A549 and CNE‐2Z tumor cells. And it demonstrated more effective anti‐tumor activity for CNE‐2Z than for A549 cells. This study marks a significant milestone, representing the inaugural endeavor to elucidate the improvement in loading capacity through the strategic extension of the π‐conjugated system design paradigm.

Advances in nanoparticle-based drug delivery in cancer treatment

As a pathologically heterogeneous disease, cancer is one of the leading causes of global morbidity. According to the World Health Organization, approximately one in six deaths are caused by cancer. Fortunately, many cancers can be cured if diagnosed at early stages and treated efficiently. Despite the benefits of conventional cancer treatments such as surgery, chemotherapy, hormone therapy, and radiation therapy, they have several drawbacks, including cytotoxicity, inaccurate targeting of tumor cells, and multi-drug resistance, which underscore the importance of developing novel and effective strategies to improve diagnosis, prognosis, therapy, and patient survival. Recently, the advancement of nanotechnology has opened new horizons for cancer treatment thanks to the discovery of nanoparticles (NPs) and the small-sized molecules that revolutionized the drug delivery methods in cancerous tissues. The specific characteristics of NPs, such as reduced toxicity, improved permeability, and accurate targeting of tumor cells, provide a great advantage in cancer treatment and help to overcome the limitations and challenges of conventional cancer treatment methods. Besides, the role of NPs in immunotherapy has created a novel concept for cancer treatment. This review gives a brief overview regarding the importance of NPs and their targeting mechanism, as well as the challenges and limitations associated with their use in cancer treatment.

Dual Drug-Loaded Nanoliposomes Encapsulating Curcumin and 5-Fluorouracil with Advanced Medicinal Applications: Self-Monitoring and Antitumor Therapy.

Due to the presence of physiological barriers, it is difficult to achieve the desired therapeutic efficacy of drugs; thus, it is necessary to develop an efficient drug delivery system that enables advanced functions such as self-monitoring. Curcumin (CUR) is a naturally functional polyphenol whose effectiveness is limited by poor solubility and low bioavailability, and its natural fluorescent properties are often overlooked. Therefore, we aimed to improve the antitumor activity and drug uptake monitoring by simultaneously delivering CUR and 5-Fluorouracil (5-FU) in the form of liposomes. In this study, dual drug-loaded liposomes (FC-DP-Lip) encapsulating CUR and 5-FU were prepared by the thin-film hydration method; their physicochemical properties were characterized; and their biosafety, drug uptake distribution in vivo, and tumor cell toxicity were evaluated. The results showed that the nanoliposome FC-DP-Lip showed good morphology, stability, and drug encapsulation efficiency. It showed good biocompatibility, with no side effects on zebrafish embryonic development. In vivo uptake in zebrafish showed that FC-DP-Lip has a long circulation time and presents gastrointestinal accumulation. In addition, FC-DP-Lip was cytotoxic against a variety of cancer cells. This work showed that FC-DP-Lip nanoliposomes can enhance the toxicity of 5-FU to cancer cells, demonstrating safety and efficiency, and enabling real-time self-monitoring functions.

Abstract 4122: TIL-containing patient-derived explant cultures reveal role of metformin on antigen presenting cell activation

Abstract Globally, breast cancer is among the most diagnosed cancer types for women. Current and upcoming breast cancer therapies are being investigated in combination with compounds that stimulate an immune response, but whether the therapeutic agents themselves have unexpected immunomodulatory effects is often overlooked. Here, we have developed a method to grow 3D cultures of intact fragments of patient-derived tissue (Patient-Derived Explant Cultures; PDECs) to assess the preclinical potential of studying human tumor cells and immune cells simultaneously ex vivo Single cell sequencing, flow cytometry, gene expression profiling and cytokine profiling data show that the tumor immunocontexture is conserved in PDECs and that these resident immune cells respond to distinct immune stimulus We performed gene expression profiling, flow cytometry, and cytokine profiling of drug-treated human explants and found that metformin has antitumor potential through the activation of antigen presenting cells. We further validated in vitro that metformin-mediated APC activation is largely through mitochondrial respiration inhibition irrespective of the presence of tumor cells. Our PDEC platform highlights the preclinical potential of ex vivo explants by simultaneously offering information of tumor and immune cell toxicity and mechanism. Citation Format: Rita J. Turpin, Ruixian Liu, Pauliina Munne, Aino Peura, Jenna Rannikko, Gino Philips, Natasha Salmelin, Elina Hurskainen, Ilida Suleymanova, Minna Mutka, Tuomo Meretoja, Johanna Mattson, Satu Mustjoki, Päivi Saavalainen, Diether Lambrechts, Jeroen Pouwels, Maija Hollmén, Juha Klefström. TIL-containing patient-derived explant cultures reveal role of metformin on antigen presenting cell activation. [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 4122.

Regulating tumor cholesterol microenvironment to enhance photoimmunotherapy in oral squamous cell carcinoma

Regulating tumor cholesterol microenvironment to enhance photoimmunotherapy in oral squamous cell carcinoma

Anticancer Potential of Artemisinin Derivatives Containing Fluorine Atoms

Artemisinin and its derivatives were widely used in treatment of malaria in last decades years. As a natural compound extracted from Chinese herb Artemisia annua, artemisinin and its derivatives presented high cytotoxicity to tumor cell and low toxicity to human body. If this great medicine can be used in the treatment of other disease, a new treatment will be found. Many researches were carried out to confirm these compounds can be used as a new anticancer agent. Artemisinin and its derivatives presented cytotoxicity to tumor cells were confirmed by many experiments. Besides some common derivatives which were widely used in the malaria therapy, some new artemisinin derivatives were synthesized and evaluated whether these compounds can become potential anticancer drug. There is research carried out by Shu Li and others synthesized a new type of artemisinin derivatives, artemisinin derivatives containing fluorine atoms, and evaluated these new compound’s cytotoxicity to tumor cells. In this review paper, the anticancer activity of artemisinin derivatives containing fluorine atoms were introduced and its cytotoxicity against tumor cells were shown. Then, the anticancer ability of artemisinin containing fluorine atoms and other common artemisinin derivatives: dihydroartemisinin and artesunate were compared. Finally, traditional treatment of cancer, such as chemotherapy and radiotherapy were introduced in this paper. By comparing artemisinin derivatives with traditional treatment of cancer, the big cancer-fighting potential for artemisinin and its derivatives should be see and further investigated. A new series of artemisinin derivatives, compounds containing fluorine atoms have anticancer ability too. Results obtained by literature research and read show artemisinin containing fluorine atoms may be a great potential anticancer drug but still need more exploration and practice like other artemisinin derivatives.

Folic acid conjugated carbon dots doped metal-organic framework materials for cell imaging

Folic acid conjugated carbon dots doped metal-organic framework materials for cell imaging

Chemotherapy reinforces anti-tumor immune response and enhances clinical efficacy of immune checkpoint inhibitors.

New evidence suggests that the clinical success of chemotherapy is not merely due to tumor cell toxicity but also arises from the restoration of immunosurveillance, which has been immensely neglected in previous preclinical and clinical researches. There is an urgent need for novel insights into molecular mechanisms and regimens that uplift the efficacy of immunotherapy since only a minority of cancer patients are responsive to immune checkpoint inhibitors (ICIs). Recent findings on combination therapy of chemotherapy and ICIs have shown promising results. This strategy increases tumor recognition and elimination by the host immune system while reducing immunosuppression by the tumor microenvironment. Currently, several preclinical studies are investigating molecular mechanisms that give rise to the immunomodulation by chemotherapeutic agents and exploit them in combination therapy with ICIs in order to achieve a synergistic clinical activity. In this review, we summarize studies that exhibit the capacity of conventional chemotherapeutics to elicit anti-tumor immune responses, thereby facilitating anti-tumor activities of the ICIs. In conclusion, combining chemotherapeutics with ICIs appears to be a promising approach for improving cancer treatment outcomes.

Fermented Soy Drink (Q-CAN® PLUS) Induces Apoptosis and Reduces Viability of Cancer Cells

This study tested the ability of a fermented soy product to induce tumor cell toxicity and to assess if this was due to fermentation of soy, and to the genistein content. Four cancer cell lines were cultured without additive, with fermented soy (Q-CAN® PLUS), nonfermented soy, or genistein, and cell viability was examined at 24 h, 48 h, and 72 h. The sensitivity of the cell lines to apoptosis by Q-CAN PLUS was tested with the Annexin V assay. All cell lines demonstrated a dose and time response reduction in tumor cell viability with exposure to Q-CAN PLUS (IC50 at 24 h 3.8 mg/mL to 9 mg/mL). Unfermented soy did not show reduction in viability of any cell line within the same concentration range. The IC50 of genistein for each of the cell lines was significantly greater than for Q-CAN PLUS. All four tumor cell lines demonstrated apoptosis in response to Q-CAN PLUS. Q-CAN PLUS reduces viability and increases apoptosis of cancer cells in a concentration- and fermentation-dependent manner. Taking into consideration the IC50 of genistein and the concentration of genistein in Q-CAN PLUS, the genistein content of Q-CAN PLUS is not responsible for the majority reduction in tumor cell viability. This suggests that fermentation of soy results in the production of metabolites that reduce cancer cell viability and induce cellular apoptosis, and play a major role in addition to any effects produced by their genistein content.

Dual-pH responsive chitosan nanoparticles for improving in vivo drugs delivery and chemoresistance in breast cancer

Dual-pH responsive chitosan nanoparticles for improving in vivo drugs delivery and chemoresistance in breast cancer

In vitro assessment of stearyl triphenyl phosphonium toxicity in drug-resistant tumor cells

Introduction: The triphenyl phosphonium residue is a well-documented mitochondriotropic that has been shown to improve the accumulation of biomolecules in mitochondria. Stearyl triphenyl phosphonium (STPP) modified liposomes have been shown to facilitate the selective accumulation of various biomolecules in mitochondria resulting in improved effect in-vitro and in-vivo. More recently, STPP was reported to have higher toxicity towards a drug resistant ovarian cancer cell line compare to a non-drug resistant cell line. The purpose of this study was to further investigate STPP toxicity using multiple drug resistant and non-drug resistant cell lines. Methods: STPP was incorporated into phosphatidylcholine cholesterol liposomes using the thin film hydration method. Mean particle size and zeta potential was measured using dynamic light scattering. The 5,5,6,6′-tetrachloro-1,1′,3,3′ tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) dye accumulation assay was used as an indicator of mitochondrial membrane potential in the tested cell lines. Cytotoxicity of the preparations towards different cell lines was determined using light microscopy and the CellTiter 96® AQueous One Solution Cell Proliferation assay. Results: The JC-1 accumulation assay confirmed that the drug-resistant cell lines had significantly higher dye accumulation than the non-drug resistant cell lines. Higher cytotoxicity of STPP towards drug resistant cell line was seen when incorporated into liposomes but not when dissolved in dimethyl sulfoxide (DMSO). STPP showed a comparable toxicity profile to the known oxidative phosphorylation uncoupler carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone (FCCP). Discussion: Taken together, the data suggest that higher STPP toxicity in the drug-resistant cell lines is influenced by the presence of liposomal lipids and that STPP acts in a way similar to an oxidative phosphorylation uncoupler and is therefore more toxic to the drug-resistant cells that rely on a higher mitochondrial membrane potential to maintain their viability.

Cytotoxic Effect In Vitro of Acalypha monostachya Extracts over Human Tumor Cell Lines.

Acalypha monostachya (A. monostachya) is a plant that is used in traditional medicine as a cancer treatment; however, its effect has not been validated. In this study, the potential cytotoxic effects and morphological changes of A. monostachya were evaluated in human tumor cell lines. The aqueous (AE), methanolic (ME), and hexane (HE) extracts were obtained, and flavonoid-type phenolic compounds were detected, which indicates an antineoplastic effect. We observed a time-dependent and concentration-selective toxicity in human tumor cells. Additionally, the ME and HE showed the greatest cytotoxic effect at minimum concentrations compared to the AE, which showed this effect at the highest concentrations. All extracts induced significant morphological changes in tumor cells. The HeLa (cervix carcinoma) cells were more sensitive compared to the MDA-MB-231 (triple-negative breast cancer) cells. In conclusion, we demonstrated a cytotoxic in vitro effect of A. monostachya extracts in tumoral human cell lines. These results show the potential antineoplastic effects of A. monostachya in vitro. Hereafter, our lab team will continue working to usefully isolate and obtain the specific compounds of A. monostachya extracts with cytotoxic effects on tumor cells to find more alternatives for cancer treatment.

Brain Distribution of Berzosertib: An Ataxia Telangiectasia and Rad3-Related Protein Inhibitor for the Treatment of Glioblastoma.

Brain Distribution of Berzosertib: An Ataxia Telangiectasia and Rad3-Related Protein Inhibitor for the Treatment of Glioblastoma.

Gas-filled protein nanostructures as cavitation nuclei for molecule-specific sonodynamic therapy

Gas-filled protein nanostructures as cavitation nuclei for molecule-specific sonodynamic therapy