Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Sept. 12, 2022

Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving therapeutic potential various agents and bioactive molecules through enhanced permeability retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective tumor cells utilizing cell surface-specific receptors, vasculature antigens high accuracy affinity. Additionally, stimuli-responsive nanoplatforms also been as a promising strategy against tumors, these maintain their stealth feature under conditions, but upon homing cancerous lesions or microenvironment, are responsive release cargoes. In this review, we comprehensively summarize field active number studies context emerging nanoplatform development, discuss how knowledge contribute further improvements clinical practice.

Language: Английский

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Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 18, 2022

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cells response to therapy-induced hostile environment are largely unknown. As central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes integrate signaling pathways provide bioenergetic biosynthetic flexibility cells, which contributes multiple aspects tumor characteristics, including drug resistance. Therefore, targeting therapy overcoming has attracted increasing attention various types cancer. Multiple mitochondrial processes, dynamics, metabolism, apoptotic regulatory machinery, have been demonstrated be potential targets. However, recent insights into revealed complexity structure functions, elusive functions biology, inaccessibility mitochondria, posed challenges clinical application mitochondrial-based therapeutic strategies. discovery both novel mitochondria-targeting agents innovative approaches is urgently required. Here, we review most literature summarize molecular their intricate connection with In addition, an overview emerging strategies target effectively chemoresistance highlighted, emphasis on repositioning delivery approaches, may accelerate compounds therapy.

Language: Английский

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Drug-induced oxidative stress in cancer treatments: Angel or devil?

Redox Biology, Journal Year: 2023, Volume and Issue: 63, P. 102754 - 102754

Published: May 18, 2023

Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one the most significant biological events cancer progression. Cancer cells generally represent a higher level, which suggests dual therapeutic strategy by regulating status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, exhibits great anti-cancer capability, attributing to accumulation within cells, whereas restore homeostasis has been claimed fail several clinical practices. Targeting vulnerability pro-oxidants capable generating excessive reactive oxygen species (ROS) surfaced an important strategy. However, multiple adverse effects caused indiscriminate attacks uncontrolled drug-induced OS on normal tissues and drug-tolerant capacity some certain greatly limit their further applications. Herein, we review representative oxidative drugs summarize side organs, emphasizing that seeking balance between damage value exploiting next-generation OS-based chemotherapeutics.

Language: Английский

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Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

MedComm, Journal Year: 2022, Volume and Issue: 3(2)

Published: May 18, 2022

Abstract Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties invasive ability. Originally defined as an embryogenesis event, EMT has been recognized crucial process in tumor progression. During EMT, cell–cell cell–matrix attachments are disrupted, the cytoskeleton remodeled to enhance mobility of cells. This phenotype largely driven by group key transcription factors, typically Snail, Twist, ZEB, through epigenetic repression markers, transcriptional activation matrix metalloproteinases, reorganization cytoskeleton. Mechanistically, orchestrated multiple pathways, especially those involved such TGFβ, Wnt, Hedgehog, Hippo, suggesting intrinsic link between embryonic development cancer In addition, redox signaling also emerged critical modulator. confers with increased metastatic potential drug resistant capacity, which accounts for recurrence most clinic cases. Thus, targeting can be therapeutic option providing chance cure patients. Here, we introduce brief history summarize recent advances understanding mechanisms, well highlighting opportunities treatment.

Language: Английский

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Circadian rhythms and cancers: the intrinsic links and therapeutic potentials

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: March 4, 2022

The circadian rhythm is an evolutionarily conserved time-keeping system that comprises a wide variety of processes including sleep-wake cycles, eating-fasting and activity-rest coordinating the behavior physiology all organs for whole-body homeostasis. Acute disruption may lead to transient discomfort, whereas long-term irregular will result in dysfunction organism, therefore increasing risks numerous diseases especially cancers. Indeed, both epidemiological experimental evidence has demonstrated intrinsic link between dysregulated cancer. Accordingly, rapidly understanding molecular mechanisms rhythms opening new options cancer therapy, possibly by modulating clock. In this review, we first describe general regulators their functions on addition, provide insights into underlying how several types (including sleep-wake, eating-fasting, activity-rest) can drive progression, which expand our development from clock perspective. Moreover, also summarize potential applications treatment, optional therapeutic strategy patients.

Language: Английский

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Redox signaling at the crossroads of human health and disease

MedComm, Journal Year: 2022, Volume and Issue: 3(2)

Published: March 31, 2022

Abstract Redox biology is at the core of life sciences, accompanied by close correlation redox processes with biological activities. homeostasis a prerequisite for human health, in which physiological levels nonradical reactive oxygen species (ROS) function as primary second messengers to modulate signaling orchestrating multiple sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads biomolecule damage and subsequent occurrence various diseases such type 2 diabetes, atherosclerosis, cancer. Herein, starting evolution biology, we reveal roles multifaceted modulators mediate sustain homeostasis. In addition, also emphasize detailed OS mechanisms involved initiation development several important diseases. double‐edged sword disease progression suggest two different therapeutic strategies treat redox‐relevant diseases, targeting sources redox‐related effectors manipulate will largely promote precision medicine. Therefore, comprehensive understanding networks under pathological conditions facilitate medicine benefit patients

Language: Английский

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Drug-tolerant persister cells in cancer: the cutting edges and future directions

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(11), P. 799 - 813

Published: Sept. 25, 2023

Language: Английский

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TGF-β, EMT, and resistance to anti-cancer treatment

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 97, P. 1 - 11

Published: Nov. 8, 2023

Transforming growth factor-β (TGF-β) signaling regulates cell-specific programs involved in embryonic development, wound-healing, and immune homeostasis. Yet, during tumor progression, these TGF-β-mediated are altered, leading to epithelial cell plasticity a reprogramming of cells into mesenchymal lineages through epithelial-to-mesenchymal transition (EMT), critical developmental program morphogenesis organogenesis. These changes, turn, lead enhanced carcinoma invasion, metastasis, differentiation, evasion, chemotherapy resistance. Here, we discuss EMT as one the associated with influence exerted by TGF-β on status function. We further explore composition other populations within microenvironment, consider relevant outcomes related cancer treatment

Language: Английский

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Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies

MedComm – Oncology, Journal Year: 2025, Volume and Issue: 4(1)

Published: Jan. 10, 2025

Abstract The success of cancer therapy has been significantly hampered by various mechanisms therapeutic resistance. Chief among these is the presence clonal heterogeneity within an individual tumor mass. introduction concept stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding drug Given characteristics CSCs, such as increased drug‐efflux activity, enhanced DNA‐repair capacity, high metabolic plasticity, adaptability oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have recognized a theoretical reservoir for resistant diseases. Implicit in this recognition possibility CSC‐targeted strategies might offer breakthrough overcoming resistance patients. Herein, we summarize generation current underlying CSC‐mediated This extended knowledge progressively translated into novel anticancer enriched available options combination treatments, all which are anticipated improve clinical outcomes patients experiencing CSC‐related relapse.

Language: Английский

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Inhibition of NPC1L1 disrupts adaptive responses of drug‐tolerant persister cells to chemotherapy

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(2)

Published: Jan. 13, 2022

Article13 January 2022Open Access Source DataTransparent process Inhibition of NPC1L1 disrupts adaptive responses drug-tolerant persister cells to chemotherapy Zhe Zhang orcid.org/0000-0001-7509-6965 Laboratory Aging Research and Cancer Drug Target, State Key Biotherapy Center, National Clinical Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, School Basic Medical Sciences & Forensic Medicine, Collaborative Innovation Biotherapy, Contribution: Conceptualization, Data curation, Visualization, Writing - original draft, review editing Search more papers by this author Siyuan Qin Methodology Yan Chen Li Zhou curation Mei Yang orcid.org/0000-0002-0423-6358 Yongquan Tang Department Pediatric Surgery, Jing Zuo Jian Southern University Science Technology Shenzhen, Guangdong, Guangdong Provincial Cell Microenvironment Disease Research, Atsushi Mizokami Urology, Graduate Sciences, Kanazawa Kanazawa, Japan Edouard C Nice Biochemistry Molecular Biology, Monash Clayton, Vic, Australia Supervision, Hai-Ning Corresponding Author [email protected] orcid.org/0000-0003-0104-8498 Gastrointestinal Funding acquisition, Methodology, Canhua Huang orcid.org/0000-0003-2247-7750 Validation, Project administration Xiawei Wei orcid.org/0000-0002-6513-6422 administration, Information Zhang1,2,†, Qin2,†, Chen2,†, Zhou2, Yang2, Tang3, Zuo2, Zhang4,5, Mizokami6, Nice7, *,8, *,2 *,1 1Laboratory 2State 3Department 4School 5Guangdong 6Department 7Department 8Department † These authors contributed equally work *Corresponding author. Tel: +86 18980606468; E-mail: 13258370346; 18081954096; EMBO Mol Med (2022)14:e14903https://doi.org/10.15252/emmm.202114903 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Entering (DTP) state cancer is transient self-adaptive mechanism which residual cell subpopulation accelerates tumor progression. Here, we identified acquisition DTP phenotype in multidrug-resistant (MDR) as tolerance response routine combination treatment. Characterization MDR with RNA-seq revealed that these partially prevented chemotherapy-triggered oxidative stress promoting NPC1L1-regulated uptake vitamin E. Treatment inhibitor ezetimibe further enhanced therapeutic effect combinatorial therapy inducing methuosis. Mechanistically, demonstrated NRF2 was involved transcriptional regulation binding −205 −215 bp site on its promoter. Decreased DNA methylation also related process. Furthermore, confirmed triple-combination chemotherapeutic agents, verapamil, ezetimibe, had significant anti-tumor recurrence mice. Together, our study provides novel insight into role emphasizes importance disrupting redox homeostasis during therapy. Synopsis Drug-tolerant driver failure relapse. This key state, where orchestrated signaling against harsh environment caused possess stronger capacity enter than non-resistant cells. supporter counter therapy-induced inhibition interrupts E cholesterol, triggering lipid ROS accumulation consequent lipotoxicity agents/verapamil treatment A exerts prevents The paper explained Problem mostly due occurrence multidrug resistance (MDR). subset exhibits entering after emerging concept explains generation resistant clones clinically relevant MDR. Accordingly, exploring specific behavior current important delaying or even eradicating targeting vulnerabilities. Results We MDR1-mediated agents MDR1 verapamil. survived chemotherapy-induced primarily scavenging through NRF2-NPC1L1 axis-regulated uptake. Based nanoparticle-related drug delivery systems alleviate verapamil side effects vivo, Impact Our bearings relationship between NPC1L1-modulated defense using cells, establishes strategy treating preventing recurrence. Introduction resistance, either intrinsic acquired, omnipresent clinical cancer, limiting durable benefits accelerating metastasis (Szakacs et al, 2006; Andrei 2020; Dallavalle 2020). Multidrug one most difficult problems occurring chemotherapy, commonly expression ATP-binding cassette (ABC) transporters, especially transporter—multidrug protein 1 (MDR1) encoded ABCB1 (Hall 2009). Along emergence appropriate analytical tools, advanced medicinal techniques, multidisciplinary research, ample evidence not only identifies high portending poor adverse outcomes patients cancers but confirms necessity applying new protocols prevent clinic (Fan 2017). Unfortunately, growing realization rather being sensitive resistant, can be dynamic nature within context detracting from such studies (Qin There actually, particular lying sensitivity termed "drug-tolerant state," population endowed dormant, slow-cycling stem-like signature (Shen 2019, originates an early observation bacterial antibiotics, existence bacteria exposed antibiotics non-genetic variations resumption their initial characteristics upon interruption (Balaban 2019). In share similar situation is, fashion antibiotic driven epigenetic inheritance variant gene patterns. could result inhibiting efficacy providing reservoir evolution Given has been hypothesized part alternative approach toward bona fide mechanism, line research attracting considerable attention. addition recognition serve target (i.e., incorporation modulator), focusing have deepened understanding mechanisms driving DTP. encourages development methods aimed at disposing sustaining harmless dormant reactivating proliferation enhance anti-proliferative drugs eradicate them (Recasens Munoz, However, there remains some confusion how best indicating requirement both itself DTP-mediated order devise countermeasures persisters. To date, multiple emphasized impact generation, several teams highlighted adapt common characteristic (Raha 2014; Sahu 2016; Hangauer 2017; Anand 2019; Dhimolea 2021). characteristic, increasing numbers targets investigated. Among phospholipid glutathione peroxidase 4 (GPX4) crucial survival therapy-resistant state. context, subsequent shown GPX4-dependent almost completely induction ferroptosis, death, suggesting potential disturbing (Hangauer Additionally, activated NF-E2-related factor 2 (NRF2), detected HER2-inhibited persistent breast found drive re-establishment metabolism-dependent manner, thereby reactivation triggered glutaminase inhibition. impair growth recurrent tumors levels NRF2, treat (Fox Such findings confirm adaption stress. might raise robust antioxidant system resisting (Trachootham therefore questioned whether arising prefer orchestrate evolutionarily conserved study, investigated characterized overexpression underwent (chemotherapeutic agent verapamil)-induced gain alterations profile course non-mutationally acquired performed comparing function screened genes status. NPC1L1, regulator interact directly peroxyl radicals, thus stress, highly expressed By adding therapy, absorption compromised additional death observed consequence macropinocytosis induction. results link activation decreased expression. Using nanomedicine triple-combinatorial (a ezetimibe) vivo. progresses persistence perspective, repositioning Oncotherapy induces transformation elucidate molecular underlying established drug-resistant models (Du145TXR taxol; MCF-7ADR adriamycin) (Appendix Fig S1A B), first examined (also known p-glycoprotein), extensively studied (Gouaze 2005; Takeda 2007; Robey 2018) marked upregulation S1C). determined played regulating rhodamine123 substrate MDR1) Fluorescence analysis indicated expressing showed increased efflux compared control reverse S1D). investigate anti-cancer ability synergistic effects, viability Chou–Talalay method (combination index (CI) < representing synergism) different combination-treated 50 μM combined 20 nM taxol 200 adriamycin exhibited beneficial Du145TXR S1E F). significantly inhibited under treatment, evidenced reduced colony formation S2A B). Consistently, knockdown clearly clonogenic chemotherapy-treated S2C–G). Together previous reports, data support establish MDR1, least part, enables recover chemosensitivity. Notably, following were those described survive cytotoxic exposure via reversible non-mutational mechanisms. evaluate associated morphological changes (50 verapamil/20 adriamycin). Surprisingly, (MCs), treated (RMCs) dramatic 3 days obvious second applied 1, 3, 6, 9 withdrawal assay (Fig 1A–D). Subsequently, long-term "drug holiday" (30 days) allowed regrow (regrown RCs) resulted re-acquisition 1E). reversibility implies oncotherapy drives (MPCs). compare differences MPCs (PeCs), used protocol generate (CCs) EV1A). prolonged > small EV1B–D). addition, progressively re-acquired eventually became non-differential Day 6 EV1E converted above obtained assays (Figs 1C–E EV1C–F) rate. As 1F G, evolve faster longer duration Taken together, demonstrate transform resembling possibly leading worse outcome modest reversal Figure 1. A. Schematic analyses. circular arrow represents B. Phase contrast images regrown MCF-7ADR. Red circles mark magnified areas (bottom). Scale bars, μm (low magnification images). C, D. (MCs) (C) (D) same 24 h days. Student's t-test analyze statistical differences. Mean ± SD. (RCs) (left) (right) h. F, G. rate (F) Du145/Du145TXR (20 taxol/20 plus verapamil) (G) MCF-7/MCF-7ADR (200 adriamycin/200 defined followed RMCs vs. MCs CCs PeCs, tolerant. Induction time indicates state; maintaining Blue colors represent groups; information: are representative three independent experiments. available online figure. [emmm202114903-sup-0004-SDataFig1.jpg] Download figure PowerPoint Click here expand EV1. Control states change Du145 MCF-7 72 bar, (low-magnification (CCs), (CCs-3), (PeCs) concentrations (TAX) (ADM) E, F. CCs, withdrawn PeCs (PeCs-3), (PeCs-6) (E) Upregulation supports well-known cycle arrest, stemness markers, well epithelial–mesenchymal transition (EMT) 2020), phenotypes. seemed increases p27 p21 S3A). flow cytometry arrest G0/G1 phase induced MPCs, showing non-proliferative slowly proliferative S3B–D). markers ALDH1A1, Oct-4A, Sox2, KLF4, CD44 sphere self-renewal stemness, increase number size spheres S3E–G). Interestingly, ALDH1A1 CM10 selectively lethal sensitized consistent Appendix S3H–J). characteristics, downregulat

Language: Английский

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