Induction Of Apoptosis In Cancer Cells Research Articles

Taraxasterol Inhibits Tumor Growth by Inducing Apoptosis and Modulating the Tumor Microenvironment in Non-Small Cell Lung Cancer.

Simple SummaryTaraxasterol (TAX) demonstrates strong pharmacological activity in some diseases. In this study, we demonstrate that TAX induces S-phase cell cycle arrest, prevents cell migration by interfering EMT, and induces cancer cell apoptosis. In addition, TAX administration downregulated the proportion of Treg cells and upregulated CD107a + NK cells in TME. Our in vitro and in vivo findings indicate that TAX could serve as a potential natural drug for lung cancer therapy.Taraxasterol (TAX), one of the active components in Dandelion, demonstrated strong antitumor properties in several cancers. However, the effect and underlying mechanism of TAX in non-small cell lung cancer (NSCLC) is unclear. In this study, we showed that TAX inhibited the proliferation of cells by inducing S-phase cell cycle arrest and prevented cell migration by interfering epithelial-mesenchymal transition (EMT) in Lewis lung cancer (LLC) cells and lung carcinoma SPC-A1 cells. The pharmacological network analysis predicted that induction of apoptosis might be the potential mechanism of TAX-mediated cell deaths. Further in vitro experiments showed that TAX could significantly induce cancer cell apoptosis as verified by increased pro-apoptotic molecules including Bax, caspase-9, and PARP1 downregulated anti-apoptotic protein Bcl-2; and decreased mitochondrial potential. The LLC subcutaneous tumor model demonstrated that TAX inhibited tumor growth by induction of apoptosis and inhibition of proliferation in vivo, which is consistent with the in vitro data. Importantly, TAX administration downregulated the proportion of Treg cells and upregulated CD107a+ NK cells in the tumor microenvironment in the tumor model. Together, these data reveal that TAX performs its antitumor effect by inducing apoptosis and modulating the tumor microenvironment, providing evidence that TAX could serve as a potential natural drug for lung cancer therapy.

IRGD-grafted N-trimethyl chitosan-coated protein nanotubes enhanced the anticancer efficacy of curcumin and melittin

Curcumin (Cur) and Melittin (Mel) are two natural extracts that have been shown anti-tumor effects. However, their applications are limited due to poor oral bioavailability and the lack of tumor-targeting property. Here, we developed a novel nanocomposite that enabled the co-delivery of Cur and Mel, which consists of α-lactalbumin protein nanotubes (NTs), positively charged N,N,N-trimethyl chitosan (TMC), and a tumor-targeting cyclic peptide iRGD. The results showed that NTs/Cur-TMC-Mel-iRGD incorporated the advantages of each component, for instance, effective compounds loading by NTs, improved cellular uptake by TMC, prolonged accumulation in tumors by iRGD as well as synergistic anti-tumor effects of Cur and Mel. In the tumor-bearing mice, NTs/Cur-TMC-Mel-iRGD treatment remarkably induced cancer cell apoptosis while inhibiting cell proliferation, leading to suppressed tumor growth. Besides, no obvious adverse effects were observed in the blood physiology and tissue histology. Overall, our study provided an effective strategy for co-delivering Cur and Mel, which has a potential for translational clinical research aiming to treat solid tumors.

Tumor Response and NIR‐II Photonic Thermal Co‐Enhanced Catalytic Therapy Based on Single‐Atom Manganese Nanozyme

AbstractSingle‐atom nanozymes (SAzymes) can effectively mimic the metal active centers of natural enzymes at the atomic level owing to their atomically dispersed active sites, thereby maximizing atom utilization efficiency and density of active sites. Hence, SAzymes can be considered the most promising candidates to replace natural enzymes. Herein, a PEGylated mesoporous Mn‐based single‐atom nanozyme (PmMn/SAE) employing a coordination‐assisted polymerization pyrolysis strategy that uses polydopamine for photothermal‐augmented nanocatalytic therapy is designed. PmMn/SAE exhibits excellent multiple enzymatic performance, including catalase‐like, oxidase‐like, and peroxidase (POD)‐like performance, due to the atomically dispersed Mn active species. As a result, PmMn/SAE not only catalyzes the decomposition of endogenous H2O2to generate O2for relieving hypoxia inside the tumor but also transfers electrons to O2to produce superoxide radicals to kill tumor cells. Meanwhile, PmMn/SAE is able to trigger Fenton‐like reactions to generate highly toxic hydroxyl radicals to induce cancer cell apoptosis. The POD‐like catalytic mechanism of mMn/SAE is revealed using experimental results and density functional theory. Furthermor, PmMn/SAE shows good photothermal conversion efficiency (η = 22.1%) in the second near‐infrared region (1064 nm). Both the in vitro and in vivo experimental results indicate that PmMn/SAE can effectively kill cancer cells through photothermal‐enhanced catalytic therapy.

Amino porphyrin-peptide assemblies induce ribosome damage and cancer stem cell inhibition for an enhanced photodynamic therapy

Cancer stem cells (CSCs) are the subpopulation of tumor cells with the properties of tumorigenesis, multilineage differentiation potential and self-renewal, which is the driving force of tumor recurrence and metastasis. However, targeting CSCs is still the main challenge in cancer therapy due to their rapid growth and fast mutation rate. Herein, we developed a simple strategy of photodynamic therapy (PDT) targeting CSCs, dependent on much more abundant ribosomes in CSCs. The interactions between positively charged nanoparticles with negatively charged nucleic acids architectures in cancer cells could lead ribosomes targeting as well as CSCs targeting. The co-assembly of simple amino porphyrin (m-TAPP) with short peptide (Fmoc-L3-OMe) formed nanoparticles (NPs) with good biocompatibility and photoactivity, became positively charged due to low pH value of tumour microenvironment, and efficiently accessed cancer cell ribosome, approached cancer cell nuclei, therefore enriched in the fast-amplifying CSCs. The inhibitive effect on CSCs by m-TAPP assemblies was verified by the significant reduction of CSCs markers CD44, CD133 and ribosome amount in cancer cells and tissues. Upon light irradiation, the NPs induced ROS generation to provoke destructive cancer cell ribosome damage and subsequent apoptosis to prevent tumor growth markedly. Based on the assemblies of small organic molecules, our study not only achieves ribosome degradation induced cancer cells apoptosis, but also indicates new possibility of performing CSCs targeting PDT.

Dual-Modulated Release of a Cytotoxic Photosensitizer Using Photogenerated Reactive Oxygen Species and Glutathione.

Reversible thiol-disulfide exchange chemistry is of particular interest in drug delivery systems. However, high levels of glutathione (GSH) in cancer cells are hard to distinguish from GSH in normal cells, resulting in unmanageable cytotoxic drug release. This study investigates the spatiotemporally-controlled irreversible degradation of Ir-based photosensitizer (TIr3)-encapsulating nanogels (IrNG) through the hyperoxidation of resulting intracellular thiols using reactive oxygen species (ROS). A highly cytotoxic TIr3 was stably encapsulated within IrNG through hydrophobic interactions and reversible crosslinking between its disulfide bonds and thiols in the absence of light, resulting in high biocompatibility under normal cellular conditions. However, upon photoirradiation, TIr3 generated high levels of ROS, irreversibly oxidizing the thiols to induce electrostatic repulsion between the polymer molecules, resulting in the TIr3 release and induction of cancer cell apoptosis.

Dual‐Modulated Release of a Cytotoxic Photosensitizer Using Photogenerated Reactive Oxygen Species and Glutathione

AbstractReversible thiol‐disulfide exchange chemistry is of particular interest in drug delivery systems. However, high levels of glutathione (GSH) in cancer cells are hard to distinguish from GSH in normal cells, resulting in unmanageable cytotoxic drug release. This study investigates the spatiotemporally‐controlled irreversible degradation of Ir‐based photosensitizer (TIr3)‐encapsulating nanogels (IrNG) through the hyperoxidation of resulting intracellular thiols using reactive oxygen species (ROS). A highly cytotoxic TIr3 was stably encapsulated within IrNG through hydrophobic interactions and reversible crosslinking between its disulfide bonds and thiols in the absence of light, resulting in high biocompatibility under normal cellular conditions. However, upon photoirradiation, TIr3 generated high levels of ROS, irreversibly oxidizing the thiols to induce electrostatic repulsion between the polymer molecules, resulting in the TIr3 release and induction of cancer cell apoptosis.

Osthole: An up-to-date review of its anticancer potential and mechanisms of action.

With its high incidence and mortality rates, cancer is one of the largest health problems worldwide. Investigating various cancer treatment options has been the focus of many domestic and international researchers, and significant progress has been made in the study of the anticancer effects of traditional Chinese medicines. Osthole, a coumarin compound extracted from Cnidium monnieri (L.) Cuss., has become a new research hotspot. There have been many reports on its anticancer effects, and recent studies have elucidated that its underlying mechanism of action mainly involves inhibiting cancer cell proliferation, inducing cancer cell apoptosis, inhibiting invasion and migration of cancer cells, inhibiting cancer angiogenesis, increasing sensitivity to chemotherapy drugs, and reversing multidrug resistance of cancer cells. This mini-review summarizes the research progress on the anticancer effects of osthole in recent years.

Baicalein Induces Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts through Inactivation of the PI3K/Akt/mTOR Pathway.

Purpose Rheumatoid arthritis (RA) shows abnormal proliferation, apoptosis, and invasion in fibroblast-like synoviocytes (FLSs). Baicalein (BAI), extracted from Scutellaria baicalensis, is used as an anticancer drug through inducing cancer cells apoptosis. However, the mechanism of BAI in RA progression still remains unknown. Here, we demonstrated that BAI inhibited FLS proliferation and migration, whereas it enhanced apoptosis via the PI3K/Akt/mTOR pathway in vitro. Methods Cell viability and colony formation were analyzed by MTT and plate colony formation assays in SW982 cells, respectively. Apoptosis was detected by flow cytometry and western blotting. Epithelial-mesenchymal transition (EMT), MMP family proteins (MMP2/9), and the PI3K/Akt/mTOR pathway were detected by western blot. Cell migration was detected by scratch healing assay under BAI treatment in SW982 cells. Results BAI dose-dependently inhibited cell viability and colony forming in SW982 cells. BAI upregulated apoptotic proteins and downregulated EMT-related proteins, resulting in enhanced cell apoptosis and inhibited cell migration in SW982 cells. BAI also dose-dependently inhibited the phosphorylation of PI3K, Akt, and mTOR. Conclusions These results indicated that BAI inhibited FLSs proliferation and EMT, whereas induced cell apoptosis through blocking the PI3K/Akt/mTOR pathway, supporting clinical application for RA progression.

Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist.

Inhibitor of apoptosis protein (IAP) is a class of E3 ubiquitin ligases functioning to support cancer survival and growth. Many small-molecule IAP antagonists have been developed, aiming to degrade IAP proteins to kill cancer. We have evaluated the effect of lipopolysaccharide (LPS), a component of the bacterial outer membrane, on IAP antagonists in treating breast cancer in a mouse model to guide future clinical trials. We show that LPS promotes IAP antagonist-induced regression of triple-negative breast cancer (TNBC) from MDA-MB-231 cells in immunodeficient mice. IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. The apoptosis caused by LPS plus SM-164 is blocked by toll-like receptor 4 (TLR4) or MyD88 inhibitor, which inhibits LPS-induced TNFα production by the cancer cells. Consistent with this, MDA-MB-231 cell apoptosis induced by LPS plus SM-164 is also blocked by the TNF inhibitor. LPS alone does not kill MDA-MB-231 cells because it markedly increases the protein level of cIAP1/2, which is directly associated with and stabilized by MyD88, an adaptor protein of TLR4. ER+ MCF7 breast cancer cells expressing low levels of cIAP1/2 undergo apoptosis in response to SM-164 combined with TNFα but not with LPS. Furthermore, TNFα but not LPS alone inhibits MCF7 cell growth in vitro. Consistent with these, LPS combined with SM-164, but not either of them alone, causes regression of ER+ breast cancer from MCF7 cells in immunodeficient mice. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER+ breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.

PH-sensitive, tail-modified, ester-linked ionizable cationic lipids for gene delivery.

Ionizable cationic lipids have great potential for gene delivery, yet the effect of the molecular structure of such lipids on gene delivery efficiency is an ongoing research challenge. To better understand corresponding structure-function activity relationships, we synthesized four ester-linked, pH-responsive, ionizable cationic lipids. The screened DEDM4 lipid, containing 2-ethylenedimethylamine in the headgroup and a branched-chain tail, exhibited a high delivery efficacy of plasmid DNA and siRNA in A549 cells, which was comparable with that of the commercial reagent lipofectamine 3000 (lipo3000). Moreover, because of its pKa value of 6.35 and pH-sensitivity under acidic conditions, DEDM4 could carry sufficient positive charge in the acidic environment of endosomes and interact with the endosome lumen, leading to destruction of the endomembrane and subsequent release of siRNA into the cytoplasm with endosomal escape. Furthermore, we used DEDM4 to deliver IGF-1R siRNA to induce cancer cell apoptosis, thereby leading to great tumor inhibition. More importantly, it also showed very low toxicity in vivo. These structure-activity data for DEDM4 demonstrate potential clinical applications of DEDM4-mediated gene delivery for cancer.

Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety

The B cell lymphoma protein 2 (Bcl-2) family proteins regulate cell apoptosis by participating in the endogenous apoptosis pathway. As an important anti-apoptotic protein, Myeloid cell leukemia 1 (Mcl-1) is overexpressed in a variety of tumor cells, and targeting this protein has been a promising strategy for cancer therapy. Herein, based on the 1H-indole-5-carboxylic acid structure previously discovered, we have developed a series of novel compounds with increased affinities and selectivity toward Mcl-1 through structure-based drug design. Among those compounds, 26 exerted relatively better affinity and selectivity for Mcl-1 with moderate inhibition in HL-60 cells. Mechanism studies showed that compound 26 could induce cancer cells apoptosis in an Mcl-1-dependent manner. It also exhibited good microsomal and plasma stability with acceptable pharmacokinetics profiles. Furthermore, treatment with target compound in a 4T1 xenograft mouse model significantly suppressed the tumor growth. Overall, the small molecule described herein represents a promising Mcl-1 inhibitor for further study.

PTEN/AKT signaling pathway related to hTERT downregulation and telomere shortening induced in Toxoplasma GRA16-expressing colorectal cancer cells

This study investigated whether the molecular mechanism of granule protein 16 (GRA16), a dense granule protein of Toxoplasma gondii (T. gondii) that induces cancer cell apoptosis, results in telomere shortening in cancer cells. The molecular mechanism of GRA16 responsible for regulating telomerase reverse transcriptase (hTERT) activity and telomere shortening was investigated using GRA16-transferred HCT116 human colorectal cancer cells (GRA16-stable cells). GRA16 directly decreased hTERT expression by downregulating the expression and phosphorylation of hTERT transcriptional factors accompanied by decreased expression of shelterin complex molecules. Moreover, GRA16 resulted in cancer cell death through reduction of telomerase activity which leads to telomere shortening (decreased relative ratio of telomeric repeat-amplified sequence to that of a single-copy gene) (T/S ratio)), and at the same time gamma-H2A histone family member X (γ-H2A.X) stained nucleus was increased in the cells. The molecular mechanism between GRA16 and hTERT inactivation was revealed using inhibitors for phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A) as well as siRNAs against PTEN and PP2A. hTERT dephosphorylation was induced effectively by the signaling pathway of HAUSP/PTEN/p-AKT(S473) but not by PP2A-B55/p-AKT(T308). Inhibition of the PTEN signaling pathway increased mRNA expressions in hTERT transcriptional factors, cell cycle activating factors, and apoptosis-inhibiting factors. When HCT116 cells were infected with T. gondii, the number of γ-H2A.X-stained nuclei also increased and p-hTERT/hTERT decreased as in GRA16-stable cells. Altogether, our results emphasize that GRA16 is a novel promising telomerase inhibitor that causes telomere shortening through telomerase inactivation by inducing the activation of the tumor suppressor PTEN.

A Quassinoid Diterpenoid Eurycomanone from Eurycoma longifolia Jack Exerts Anti-Cancer Effect through Autophagy Inhibition

Eurycomanone (EN) is one of the representative quassinoid diterpenoids from roots of Eurycoma longifolia Jack, a natural medicine that is widely distributed in Southeast Asia. Previous studies showed that EN induces cancer cell apoptosis and exhibits anti-cancer activity, but the molecular mechanism of EN against cancer has still not been elucidated. In this study, we examined the regulatory effect of EN on autophagy to reveal the mechanism of EN-mediated colon cancer growth inhibition. First, we found that EN is able to inhibit colon cancer cell proliferation and colony formation. The angiogenesis level in cancer cells was inhibited as well. Next, the treatment of EN led to the suppression of autophagy, which was characterized by the downregulation of the LC3-II level and the formation of GFP-LC3 puncta under EN treatment in colon cancer. Moreover, we revealed that the mTOR signaling pathway was activated by EN in a time- and concentration-dependent manner. Finally, autophagy induction protected colon cancer cells from EN treatment, suggesting that autophagy improves cell survival. Taken together, our findings revealed the mechanism of EN against colon cancer through inhibiting autophagy and angiogenesis in colon cancer, supporting that the autophagy inhibitor EN could be developed to be a novel anti-cancer agent.

Dual Glutathione Depletion Enhanced Enzyme Catalytic Activity for Hyperthermia Assisted Tumor Therapy on Semi-Metallic VSe2/Mn-CS.

Semimetallic nanomaterials as photothermal agents for bioimaging and cancer therapy have attracted tremendous interest. However, the poor photothermal stability, low biocompatibility, and single component limit their therapeutic efficiency in cancer treatment. Here, manganese-doped VSe2 semimetallic nanosheets were prepared and subsequently modified with chitosan (named VSe2/Mn-CS NSs) for combined enzyme catalytic and photothermal therapy. VSe2/Mn-CS NSs show high photothermal property with a photothermal conversion efficiency of 34.61% upon 808 nm near-infrared laser irradiation. In the tumor microenvironment, VSe2/Mn-CS NSs can convert endogenous H2O2 into lethal hydroxyl radicals (•OH) to induce cancer cell apoptosis. The interaction between glutathione (GSH) and Se-Se bonds in VSe2/Mn-CS NSs results in the depletion of GSH level, and the valence states transition of manganese ions is also beneficial for the GSH consumption. This dual depletion of GSH markedly enhances the peroxidase (POD) activity, leading to the high •OH production and the improved therapeutic effect. What is more, the T1-weighted magnetic resonance and photoacoustic imaging endow VSe2/Mn-CS NSs with the ability to guide and track the treatment process. Our study provides a research strategy for the application of semimetallic nanomaterials in cancer diagnosis and treatment.

Suppressive Effects of Siegesbeckia orientalis Ethanolic Extract on Proliferation and Migration of Hepatocellular Carcinoma Cells through Promoting Oxidative Stress, Apoptosis and Inflammatory Responses.

Previous studies have demonstrated that Siegesbeckia orientalis (SO) has a suppressive effect on the growth and migration of endometrial and cervical cancer cells. The present study examined the effect of SO ethanolic extract (SOE) on the proliferation and migration of hepatocellular carcinoma (HCC) and examined the effects of SOE on non-cancerous cells using HaCaT keratinocytes as a model. The SOE effectively inhibited the proliferation of Hepa1-6 (IC50 = 282.4 μg/mL) and HepG2 (IC50 = 344.3 μg/mL) hepatoma cells, whereas it has less cytotoxic effect on HaCaT cells (IC50 = 892.4 μg/mL). The SOE treatment increased the generation of ROS in HCC, but decreased the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase. In contrast, it reduced intracellular ROS formation and upregulated the expression of the related antioxidant enzymes in the H2O2-stimulated HaCaT cells. The SOE intervention also down-regulated the anti-apoptotic Bcl-2 and the migration-related proteins including matrix metalloproteinases (MMPs) and β-catenin in the HCC, suggesting that SOE could promote HCC apoptosis and inhibit HCC migration. On the contrary, it reduced apoptosis and promoted the migration of the keratinocytes. Additionally, the SOE treatment significantly up-regulated the pro-inflammatory cytokines, including TNF-α, IL-6 and IL-1β, in Hepa1-6 and HepG2 cells. Conversely, it significantly decreased the expression of these cytokines in the H2O2-induced HaCaT cells. These findings indicated that SOE treatment can delay the progression of HCC by increasing oxidative stress, promoting inflammatory response, inducing cancer cell apoptosis and inhibiting their migration. It also has protective effects from pro-oxidant H2O2 in non-cancerous cells. Therefore, SOE may provide a potential treatment for liver cancer.

Improvement of anticancer effect of berberine by salt formation modifications

BackgroundBerberine is a quaternary isoquinoline alkaloid that possesses a significant therapeutic effect on a variety of cancers. However, due to poor bioavailability, an increased dose is often required to achieve therapeutic goals. To improve the activities of natural berberine, most modifications were focused on the positive isoquinoline unit by grafting long aliphatic chains or heterocycles. However, the negative part is ignored. At this point, the strategy of salt formation modifications with short- and medium-chain fatty acids was proposed in this article. PurposeUsing salt modification to enhance the antitumor activity of berberine and explore the mechanism. MethodsFour short- and medium-chain fatty acid salts of berberine were prepared from berberine hydrochloride by salt formation modification with the sodium salt of butyric, caproic, octanoic, and decanoic acid, respectively. The cytotoxicity of four berberine salts on B16-F10, A549, HepG2, and U373 cancer cell lines was explored. Through cell localization, Mitochondrial membrane potential assay, and Western blotting analysis explored the mechanism of berberine salt-induced apoptosis. Its anticancer activity in vivo was demonstrated by the mouse xenograft model. ResultsThe four berberine fatty acid salts exhibited an enhanced inhibitory effect on B16-F10, A549, HepG2, and U373 cancer cell lines, particularly on B16-F10 cells. Meanwhile, the four berberine fatty acid salts can inhibit the migration of B16-F10 cells. The four berberine fatty acid salts induce cancer cell apoptosis through the mitochondrial pathway, which was confirmed by the mitochondrial colocalization, the decreased mitochondrial membrane potential as well as activation of caspase-3, cytochrome C (Cyt-C), and down-regulated expression of B-cell lymphoma 2 (Bcl-2). Most importantly, the four berberine fatty acid salts inhibited tumor growth in the in vivo B16-F10 melanoma model without generating side effects intraperitoneally. ConclusionsThis study revealed that salt formation modification may be an effective strategy to optimize the anticancer property of berberine hydrochloride and demonstrated the four berberine fatty acid salts induced apoptosis through the mitochondrial apoptotic pathway.

Construction of core-in-shell Au@N-HCNs nanozymes for tumor therapy

Noble metals act as nanozymes that can generate reactive oxygen species (ROS) by catalysis to induce apoptosis of tumor cells for cancer therapy. But they are easy to aggregate, which will affect their further application. Carbon materials are often used as the carrier of noble metals to improve their catalytic performance. However, designing a composite structure to build an efficient carbon/noble metal hybrid nanozyme with high catalytic performance for tumor therapy is still a significant challenge. In this work, a core-in-shell structure nanozyme composed of gold nanoparticles (AuNPs) embedded in nitrogen-doped hollow carbon nanoshells (AuNPs@N-HCNs) were fabricated, which exhibited peroxidase-like (POD-like) and oxidase-like (OXD-like) activity. Compared with core-out-of-shell structure composite, the AuNPs@N-HCNs showed a better ability to generate ROS to kill tumor cells. Furthermore, AuNPs@N-HCNs also exhibited satisfactory photothermal conversion properties, which helped build a platform for photothermal therapy. Meanwhile, the enzyme activity produced by AuNPs@N-HCNs increased significantly under light irradiation. Comparing the size of AuNPs in carbon shell, 15 nm AuNPs were better than 2 nm in both enzyme-like activities and in vivo therapeutic effect. In vitro and in vivo studies demonstrated that under the synergistic effect of light-enhancing nanozyme catalysis and photothermal therapy, AuNPs@N-HCNs could induce cancer cell apoptosis and destroy tumors effectively, which provided evidence for the feasibility of tumor catalytic-photothermal treatment.

Research Progress on the Relationship Between Mitochondrial Deoxyguanosine Kinase and Apoptosis and Autophagy in Lung Adenocarcinoma Cells

<p>Lung cancer is the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and lung adenocarcinoma is the most common NSCLC. Most patients with lung cancer eventually lead to local and metastatic recurrence, including many patients who have completely removed the primary tumor during surgery and have no noticeable metastasis. There are two different deoxynucleotide triphosphate (dNTP) libraries in eukaryotic cells. The de novo synthesis of dNTPs in the cytoplasm is coordinated with the cell cycle and reaches a peak in the S phase, thereby providing deoxynucleotides for the replication of genomic DNA. In contrast, the mitochondrial pool of dNTPs is maintained through the mitochondrial deoxynucleoside rescue pathway throughout the cell cycle and is essential for mtDNA replication. Mitochondria are vital cell powers in assimilation and catabolism. Oxidative phosphorylation (OXPHOS) of mitochondria is essential for the self-renewal of cancer stem-like cells in lung cancer, glioblastoma and leukemia. Thymidine kinase 2 (TK2) and deoxyguanosine kinase (DGUOK) are two mitochondrial deoxynucleoside kinases, which are responsible for the transport of pyrimidine and purine deoxynucleoside in mitochondria. Apoptosis and autophagy are important processes that regulate cell proliferation and death in normal cells and cancer cells. Inducing cancer cell apoptosis and autophagy is an effective means to treat malignant tumors. This review discusses the research progress of the relationship between mitochondrial deoxyguanosine kinase and lung adenocarcinoma cell apoptosis and autophagy.</p>

Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways

The second-generation mammalian target of rapamycin (mTOR) inhibitor PP242 has demonstrated limited success in some rapamycin-insensitive tumours. We examined the therapeutic potential of combining PP242 with adenosine 50- monophosphate-activated protein kinase (AMPK) activator metformin, using a panel of colorectal carcinoma (CRC) cell lines. We found that the PP242 and metformin combination enhanced the suppression of CRC cell proliferation, colony formation, and cancer cell apoptosis induction. The effect of this combination was observed on AMPK phosphorylation. Western blotting showed that PP242 inhibited mTORC1 activation, as indicated by the reduced expression of its major substrate p-S6K1 and the partially reduced phosphorylation of eIF4E-binding protein 1 (4E-BP1). The inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT Ser473) was transient and occurred in the first few hours of PP242 treatment; metformin exposure decreased the PP242 activity, counteracting AKT activation. We further demonstrated that this was related to direct AMPK-mediated phosphorylation of IRS-1 at Ser789. Thus, the combination of PP242 and metformin completely blocked the activity of both mTORC1 and mTORC2 kinase. This study suggests that this combination could be a more effective strategy for the treatment of CRC.

Abstract 5474: A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling

Abstract Background: Mounting epidemiological and experimental evidences strongly suggest that epigenetic processes including histone modifications are involved in the development of drug resistance in breast cancer. Histone deacetylases (HDACs) selective inhibition is an important strategy of anticancer drug discovery field. However, lack of HDACs isozymes selective inhibitors associated with adverse side effects that limits their clinical applications. We have recently reported new and selective HDACs inhibitors displaying varying HDAC isozyme selectivity degrees that resulted in increased histones acetylation and apoptosis induction in cancer cells. In the present study, we investigated molecular mechanisms underlying anticancer potential of these molecules in breast cancer cells. Experimental methods: Proliferation ability, invasion capacity, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) major group’s gene expressions and protein levels, and the gelatinolytic activity of MMPs were analyzed after treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with HDACs inhibitors compounds. Results and Discussions: Two compounds, identified as MAL-4 and MAL-5, were selected based on the half-maximal inhibitory concentration (IC50) in both breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cells with 5 µM MAL-4 and MAL-5 significantly induces TIMP-2 mRNA and protein levels whereas MMP-2 and MMP-9 content and activities were reduced. Further analyses showed that MAL-4 and MAL-5 attenuated invasion capability of breast cancer cells. Conclusion: We have demonstrated that the new compounds can be used as potential lead drug candidates for an effective anti-metastatic therapy mediated by HDAC inhibition in breast cancer. Citation Format: Khuloud Bajbouj, Lina Sahnoon, Abeer AL-Ali, Jasmin Shafarin, Leonie Binder, Reem Abdul Rehman, Rafat El-Awady, Taleb H. Al-Tel. A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5474.