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Advance in Targeted Cancer Therapy and Mechanisms of Resistance

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 27933

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Special Issue Editors

Dr. Patrick Ming-Kuen Tang

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Guest Editor

Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong 999077, Hong Kong
Interests: tumor microenvironment; drug resistance; immunotherapy; cell engineering; gene therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dongmei Zhang

E-Mail Website
Guest Editor

College of Pharmacy, Jinan University, Guangzhou 510632, China
Interests: pharmacology; oncology; drug delivery; pericytes; angiogenesis; endothelial progenitor cell; extracellular vesicle; tyrosine kinase inhibitor
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would launch a special issue “Advances in Targeted Cancer Therapy and Mechanisms of Resistance“ for rapidly sharing novel findings about anti-cancer therapy and their difficulty in research to molecular aspects of all types of human cancers.

We encourage submissions of high-quality manuscripts that provide novel mechanistic insights and details of the molecular signatures of oncogenic transformation, ranging from basic sciences to preclinical research. Particularly, studies that focus on translating basic molecular knowledge to new applications in oncology are the most welcome.

The scope of this section includes, but is not limited to, the following:

Biological processes or molecular pathways for promoting development and progression of cancers
Mechanisms of primary and secondary drug resistance
Molecular interactions in the tumor microenvironment for drug response
Genomic profiling or any other ‘systems biology’ approaches in understanding acquired resistance
Research that leads to novel therapies against advanced cancers and resistance

We are looking forward to your high-quality submissions, thank you very much.

Dr. Patrick Ming Kuen Tang
Prof. Dr. Dongmei Zhang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

targeted therapy
drug resistance
tumor microenvironment
cancer progression
molecular profiling
immunosurveillance
immunotherapy
gene therapy
biomarker

Published Papers (14 papers)

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Editorial

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4 pages, 185 KiB

Open AccessEditorial

Advance in Targeted Cancer Therapy and Mechanisms of Resistance

by Patrick Ming-Kuen Tang and Dongmei Zhang

Int. J. Mol. Sci. 2023, 24(23), 16584; https://doi.org/10.3390/ijms242316584 - 22 Nov 2023

Viewed by 894

Abstract

Drug resistance remains one of the important clinical challenges, making cancer one of the leading causes of death worldwide [...] Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

Research

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31 pages, 5387 KiB

Open AccessArticle

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients

by Sawsan Elgohary, Reda A. Eissa and Hend M. El Tayebi

Int. J. Mol. Sci. 2023, 24(18), 14254; https://doi.org/10.3390/ijms241814254 - 19 Sep 2023

Cited by 2 | Viewed by 1673

Abstract

Breast cancer (BC) is not only a mass of malignant cells but also a systemic inflammatory disease. BC pro-tumorigenic inflammation has been shown to promote immune evasion and provoke BC progression. The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated when pattern recognition receptors (PRRs) sense danger signals such as calreticulin (CALR) from damaged/dying cells, leading to the secretion of interleukin-1β (IL-1β). CALR is a novel BC biological marker, and its high levels are associated with advanced tumors. NLRP3 expression is strongly correlated with an elevated proliferative index Ki67, BC progression, metastasis, and recurrence in patients with hormone receptor-positive (HR+) and triple-negative BC (TNBC). Tumor-associated macrophages (TAMs) secrete high levels of IL-1β promoting endocrine resistance in HR+ BC. Recently, an immunosuppressive soluble form of programmed death ligand 1 (sPD-L1) has been identified as a novel prognostic biomarker in triple-negative breast cancer (TNBC) patients. Interestingly, IL-1β induces sPD-L1 release. BC Patients with elevated IL-1β and sPD-L1 levels show significantly short progression-free survival. For the first time, this study aims to investigate the inhibitory impact of thymoquinone (TQ) on CALR, the NLRP3 pathway and sPD-L1 in HR+ and TNBC. Blood samples were collected from 45 patients with BC. The effect of differing TQ concentrations for different durations on the expression of CALR, NLRP3 complex components and IL-1β as well as the protein levels of sPD-L1 and IL-1β were investigated in the peripheral blood mononuclear cells (PBMCs) and TAMs of TNBC and HR+ BC patients, respectively. The findings showed that TQ significantly downregulated the expression of CALR, NLRP3 components and IL-1β together with the protein levels of secreted IL-1β and sPD-L1. The current findings demonstrated novel immunomodulatory effects of TQ, highlighting its potential role not only as an excellent adjuvant but also as a possible immunotherapeutic agent in HR+ and TNBC patients. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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20 pages, 3549 KiB

Open AccessArticle

SF3B1 Mutations Are Associated with Resistance to Non-Genotoxic MDM2 Inhibition in Chronic Lymphocytic Leukemia

by Erhan Aptullahoglu, Jonathan P. Wallis, Helen Marr, Scott Marshall, Nick Bown, Elaine Willmore and John Lunec

Int. J. Mol. Sci. 2023, 24(14), 11335; https://doi.org/10.3390/ijms241411335 - 12 Jul 2023

Cited by 2 | Viewed by 1700

Abstract

Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. There are a number of current treatment options for CLL, including monoclonal antibodies, targeted drugs, chemotherapy, and different combinations of these. However, for those patients who are intrinsically treatment resistant, or relapse following initial responses, novel targeted therapies are still needed. Targeting the mouse double-minute-2 human homolog (MDM2), a primary negative regulator of p53, is an appealing therapeutic strategy for non-genotoxic reactivation of p53, since the TP53 gene is in its wild-type state at diagnosis in approximately 90% of patients. Mutated SF3B1 and TP53 are both associated with more aggressive disease, resistance to therapies and poorer overall survival for CLL. In this study, we performed a screen for SF3B1 and TP53 mutations and tested RG7388 (idasanutlin), a second-generation MDM2 inhibitor, in a cohort of CLL primary patient samples. SF3B1 mutations were detected in 24 of 195 cases (12.3%) and found associated with poor overall survival (hazard ratio [HR] 2.12, p = 0.032) and high CD38 expression (median CD38 (%) 32 vs. 5; p = 0.0087). The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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26 pages, 2580 KiB

Open AccessArticle

SPINK2 Protein Expression Is an Independent Adverse Prognostic Marker in AML and Is Potentially Implicated in the Regulation of Ferroptosis and Immune Response

by Herbert Augustus Pitts, Chi-Keung Cheng, Joyce Sin Cheung, Murphy Ka-Hei Sun, Yuk-Lin Yung, Hoi-Yun Chan, Raymond S. M. Wong, Sze-Fai Yip, Ka-Ngai Lau, Wai Shan Wong, Radha Raghupathy, Natalie P. H. Chan and Margaret H. L. Ng

Int. J. Mol. Sci. 2023, 24(11), 9696; https://doi.org/10.3390/ijms24119696 - 2 Jun 2023

Cited by 2 | Viewed by 2466

Abstract

There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk. SPINK2 expression was associated with AML with an NPM1 mutation and an intermediate risk by cytogenetics and European LeukemiaNet (ELN) 2022 criteria. Furthermore, SPINK2 expression could refine the ELN2022prognostic stratification. Functionally, an RNA sequencing analysis uncovered a potential link of SPINK2 with ferroptosis and immune response. SPINK2 regulated the expression of certain P53 targets and ferroptosis-related genes, including SLC7A11 and STEAP3, and affected cystine uptake, intracellular iron levels and sensitivity to erastin, a specific ferroptosis inducer. Furthermore, SPINK2 inhibition consistently increased the expression of ALCAM, an immune response enhancer and promoter of T-cell activity. Additionally, we identified a potential small-molecule inhibitor of SPINK2, which requires further characterization. In summary, high SPINK2 protein expression was a potent adverse prognostic marker in AML and might represent a druggable target. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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16 pages, 2960 KiB

Open AccessArticle

A Promising Way to Overcome Temozolomide Resistance through Inhibition of Protein Neddylation in Glioblastoma Cell Lines

by Barbara Brandt, Marica Németh, Gergely Berta, Máté Szünstein, Marija Heffer, Tibor A. Rauch and Marianna Pap

Int. J. Mol. Sci. 2023, 24(9), 7929; https://doi.org/10.3390/ijms24097929 - 27 Apr 2023

Cited by 4 | Viewed by 1850

Abstract

There is no effective therapy for the lately increased incidence of glioblastoma multiforme (GBM)—the most common primary brain tumor characterized by a high degree of invasiveness and genetic heterogeneity. Currently, DNA alkylating agent temozolomide (TMZ) is the standard chemotherapy. Nevertheless, TMZ resistance is a major problem in the treatment of GBM due to numerous molecular mechanisms related to DNA damage repair, epigenetic alterations, cellular drug efflux, apoptosis-autophagy, and overactive protein neddylation. Low molecular weight inhibitors of NEDD8-activating enzyme (NAE), such as MLN4924, attenuate protein neddylation and present a promising low-toxicity anticancer agent. The aim of our study was to find an effective combination treatment with TMZ and MLN4924 in our TMZ-resistant GBM cell lines and study the effect of these combination treatments on different protein expressions such as O⁶-methylguanine methyltransferase (MGMT) and p53. The combination treatment successfully decreased cell viability and sensitized TMZ-resistant cells to TMZ, foreshadowing a new treatment strategy for GBM. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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24 pages, 4999 KiB

Open AccessArticle

Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

by Shannalee R. Martinez, Catherine C. Elix, Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Hossam R. Alkashgari, Greisha L. Ortiz-Hernandez, Lubo Zhang and Carlos A. Casiano

Int. J. Mol. Sci. 2023, 24(8), 7130; https://doi.org/10.3390/ijms24087130 - 12 Apr 2023

Cited by 7 | Viewed by 2385

Abstract

Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24– cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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17 pages, 2665 KiB

Open AccessArticle

Assessment of the Pharmacokinetics, Disposition, and Duration of Action of the Tumour-Targeting Peptide CEND-1

by Harri A. Järveläinen, Christian Schmithals, Maike von Harten, Bianca Kakoschky, Thomas J. Vogl, Stephen Harris, Claire Henson, Gemma Bullen-Clerkson and Albrecht Piiper

Int. J. Mol. Sci. 2023, 24(6), 5700; https://doi.org/10.3390/ijms24065700 - 16 Mar 2023

Cited by 3 | Viewed by 1980

Abstract

CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1’s pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [³H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [³H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [³H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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13 pages, 2292 KiB

Open AccessArticle

Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer

by Xuejun Gan, Shen Li, Yiding Wang, Hong Du, Ying Hu, Xiaofang Xing, Xiaojing Cheng, Yan Yan and Ziyu Li

Int. J. Mol. Sci. 2023, 24(6), 5482; https://doi.org/10.3390/ijms24065482 - 13 Mar 2023

Cited by 3 | Viewed by 1675

Abstract

Neoadjuvant chemotherapy (NACT) has been established as being an effective treatment for advanced gastric cancer (GC), while the predictive biomarker of NACT efficacy remains under investigation. Aspartate β-hydroxylase (ASPH) represents an attractive target which is a highly conserved transmembrane enzyme overexpressed in human GC, and participates in the malignant transformation by promoting tumor cell motility. Here, we evaluated the expression of ASPH by immunohistochemistry in 350 GC tissues (including samples for NACT) and found that ASPH expression was higher in patients undergoing NACT compared with patients without NACT pre-operation. The OS and PFS time of ASPH-intensely positive patients was significantly shorter than that of the negative patients in the NACT group, while the difference was not significant in patients without NACT. We showed that ASPH knockout enhanced the inhibitory effects of chemotherapeutic drugs on the cell proliferation, migration, and invasion in vitro and suppressed tumor progression in vivo. Co-immunoprecipitation revealed that ASPH might interact with LAPTM4B to perform chemotherapeutic drug resistance. Our results suggested that ASPH might serve as a candidate biomarker to predict prognosis and a novel therapeutic target for gastric cancer patients treated with neoadjuvant chemotherapy. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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15 pages, 5345 KiB

Open AccessArticle

by Guangzhao Huang, Su Chen, Jumpei Washio, Grace Paka Lubamba, Nobuhiro Takahashi and Chunjie Li

Int. J. Mol. Sci. 2023, 24(3), 1992; https://doi.org/10.3390/ijms24031992 - 19 Jan 2023

Cited by 8 | Viewed by 1742

Abstract

Increasing evidence suggests that aerobic glycolysis is related to the progression of oral squamous cell carcinoma (OSCC). Hence, we focused on glycolysis-related gene sets to screen for potential therapeutic targets for OSCC. The expression profiles of OSCC samples and normal controls were obtained from The Cancer Genome Atlas (TCGA). Then, the differentially expressed gene sets were selected from the official GSEA website following extraction of the differentially expressed core genes (DECGs). Subsequently, we tried to build a risk model on the basis of DECGs to predict the prognosis of OSCC patients via Cox regression analysis. Furthermore, crucial glycolysis-related genes were selected to explore their biological roles in OSCC. Two active glycolysis-related pathways were acquired and 66 DECGs were identified. Univariate Cox regression analysis showed that six genes, including HMMR, STC2, DDIT4, DEPDC1, SLC16A3, and AURKA, might be potential prognostic factors. Subsequently, a risk formula consisting of DEPDC1, DDIT4, and SLC16A3 was established on basis of the six molecules. Furthermore, DEPDC1 was proven to be related to advanced stage cancer and lymph node metastasis. Moreover, functional experiments suggested that DEPDC1 promoted the aerobic glycolysis, migration, and invasion of OSCC via the WNT/β-catenin pathway. The risk score according to glycolysis-related gene expression might be an independent prognostic factor in OSCC. In addition, DEPDC1 was identified as playing a carcinogenic role in OSCC progression, suggesting that DEPDC1 might be a novel biomarker and therapeutic target for OSCC. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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16 pages, 4084 KiB

Open AccessArticle

Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming

by Kian-Hwee Chong, Yao-Jen Chang, Wei-Hsin Hsu, Ya-Ting Tu, Yi-Ru Chen, Ming-Cheng Lee and Kuo-Wang Tsai

Int. J. Mol. Sci. 2022, 23(21), 12875; https://doi.org/10.3390/ijms232112875 - 25 Oct 2022

Cited by 11 | Viewed by 2528

Abstract

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography–mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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14 pages, 5388 KiB

Open AccessArticle

Polyphyllin I Promotes Autophagic Cell Death and Apoptosis of Colon Cancer Cells via the ROS-Inhibited AKT/mTOR Pathway

by Qihui Luo, Lanlan Jia, Chao Huang, Qi Qi, Asad Jahangir, Yu Xia, Wentao Liu, Riyi Shi, Li Tang and Zhengli Chen

Int. J. Mol. Sci. 2022, 23(16), 9368; https://doi.org/10.3390/ijms23169368 - 19 Aug 2022

Cited by 16 | Viewed by 2238

Abstract

Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 μmol/L and 3.5 ± 0.2 μmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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15 pages, 2739 KiB

Open AccessArticle

Delivery of mGluR5 siRNAs by Iron Oxide Nanocages by Alternating Magnetic Fields for Blocking Proliferation of Metastatic Osteosarcoma Cells

by Min A Kang, Pooja P. Rao, Hiroshi Matsui and Shahana S. Mahajan

Int. J. Mol. Sci. 2022, 23(14), 7944; https://doi.org/10.3390/ijms23147944 - 19 Jul 2022

Cited by 3 | Viewed by 1712

Abstract

Although osteosarcoma is the most common primary malignant bone tumor, chemotherapeutic drugs and treatment have failed to increase the five-year survival rate over the last three decades. We previously demonstrated that type 5 metabotropic glutamate receptor, mGluR5, is required to proliferate metastatic osteosarcoma cells. In this work, we delivered mGluR5 siRNAs in vitro using superparamagnetic iron oxide nanocages (IO-nanocages) as delivery vehicles and applied alternating magnetic fields (AMFs) to improve mGluR5 siRNAs release. We observed functional outcomes when mGluR5 expression is silenced in human and mouse osteosarcoma cell lines. The results elucidated that the mGluR5 siRNAs were successfully delivered by IO-nanocages and their release was enhanced by AMFs, leading to mGluR5 silencing. Moreover, we observed that the proliferation of both human and mouse osteosarcoma cells decreased significantly when mGluR5 expression was silenced in the cells. This novel magnetic siRNA delivery methodology was capable of silencing mGluR5 expression significantly in osteosarcoma cell lines under the AMFs, and our data suggested that this method can be further used in future clinical applications in cancer therapy. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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Review

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Open AccessReview

Calcium’s Role in Orchestrating Cancer Apoptosis: Mitochondrial-Centric Perspective

by Dong-Oh Moon

Int. J. Mol. Sci. 2023, 24(10), 8982; https://doi.org/10.3390/ijms24108982 - 19 May 2023

Cited by 9 | Viewed by 2175

Abstract

Calcium is an essential intracellular messenger that plays a vital role in controlling a broad range of cellular processes, including apoptosis. This review offers an in-depth analysis of calcium’s multifaceted role in apoptosis regulation, focusing on the associated signaling pathways and molecular mechanisms. We will explore calcium’s impact on apoptosis through its effects on different cellular compartments, such as the mitochondria and endoplasmic reticulum (ER), and discuss the connection between calcium homeostasis and ER stress. Additionally, we will highlight the interplay between calcium and various proteins, including calpains, calmodulin, and Bcl-2 family members, and the role of calcium in regulating caspase activation and pro-apoptotic factor release. By investigating the complex relationship between calcium and apoptosis, this review aims to deepen our comprehension of the fundamental processes, and pinpointing possible treatment options for illnesses associated with imbalanced cell death is crucial. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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9 pages, 1766 KiB

Open AccessCase Report

Gain of Aggressive Histological and Molecular Patterns after Acquired Resistance to Novel Anti-EGFR Therapies in Non-Small Cell Lung Cancer

by Clémence Basse, Olfa Trabelsi-Grati, Julien Masliah, Céline Callens, Maud Kamal, Paul Freneaux, Jerzy Klijanienko, Ivan Bieche and Nicolas Girard

Int. J. Mol. Sci. 2023, 24(4), 3802; https://doi.org/10.3390/ijms24043802 - 14 Feb 2023

Cited by 2 | Viewed by 1894

Abstract

Novel anti-EGFR therapies target resistance to standard-of-care anti-EGFR in patients with metastatic lung cancer. We describe tumors at progression versus at the initiation of novel anti-EGFR agents in patients with metastatic lung adenocarcinoma harboring EGFR mutation. This clinical case series reports the histological and genomic features and their evolution following disease progression under amivantamab or patritumab-deruxtecan in clinical trials. All patients had a biopsy at disease progression. Four patients harboring EGFR gene mutations were included. Three of them received anterior anti-EGFR treatment. Median delay to disease progression was 15 months (range: 4–24). At progression, all tumors presented a mutation in the TP53 signaling pathway associated with a loss of heterozygosis (LOH) of the allele in 75% (n = 3), and two tumors (50%) presented an RB1 mutation associated with LOH. Ki67 expression increased above 50% (range 50–90%) in all samples compared to baseline (range 10–30%), and one tumor expressed a positive neuroendocrine marker at progression. Our work reports the potential molecular mechanisms of resistance under novel anti-EGFR in patients with metastatic EGFR-mutated lung adenocarcinoma, with the transformation to a more aggressive histology with acquired TP53 mutation and/or the increase in Ki67 expression. These characteristics are usually found in aggressive Small Cell Lung Cancer. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance)

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