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Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces

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Cancer Drug Resistance 2022年第4期5卷 850-872页

作者： Ahmad R.Safa Department of pharmacology and toxicology Indiana University School of MedicineIndianapolisIN 46202USA

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality.Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stemcells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, andexpress enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell populationand lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, theirclose relationship with the tumor microenvironment creates greater complexity in developing novel treatmentstrategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCsin various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activationof various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrantDNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency ofmitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADDlikeIL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, andPI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that areunresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs.Several studies have identified promising strategies to target CSCs. These emerging strategies may help targetCSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

关键词： Cancer stem cells(CSCs) apoptosis drug resistance death receptor pathways anti-apoptotic proteins Bcl-2 family c-FLIP

Is autophagy induction by PARP inhibitors a target for therapeutic benefit?

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Oncology Research 2022年第1期30卷 1-12页

作者： AHMED M.ELSHAZLY TUONG VI V.NGUYEN DAVID A.GEWIRTZ Department of pharmacology and toxicology Virginia Commonwealth UniversityMassey Cancer CenterRichmondVA23298USA Department of pharmacology and toxicology Faculty of PharmacyKafrelsheikh UniversityKafrelsheikh33516Egypt

PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies,particularly when the tumors are deﬁcient in DNA repair pathways.However,as the case with other chemotherapeutic agents,their effectiveness is often compromised by the development of resistance.PARP inhibitors have consistently been reported to promote autophagy,a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins.Autophagy can exhibit different functional properties,the most prominent being cytoprotective.In addition,both cytotoxic and non-protective functions forms have also been identiﬁed.In this review,we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors,highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.

关键词： Olaparib Niraparib Rucaparib Talazoparib Autophagy Cytoprotective Cytotoxic Non-protective

Restoration of GABA_(B) receptor expression in cerebral ischemia:a promising novel neuroprotective strategy

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Neural Regeneration Research 2023年第12期18卷 2659-2660页

作者： Musadiq A.Bhat Mohammad Hleihil Dietmar Benke Institute of pharmacology and toxicology University of ZurichZurichSwitzerland

Although stroke is a major global health problem, a pharmacological treatment to inhibit ongoing neuronal death in patients is still lacking. In cerebral ischemia, the prevailing form of stroke, severely reduced blood supply by obstruction of blood vessels deprives neurons from oxygen and glucose, eventually leading to metabolic derailment and death of neurons in the affected brain area.

关键词： cerebral ischemia death

Cosmetic or Dietary Vegetable Oils Sampled in the Cameroonian Market May Not Expose Consumers to Lipid Oxidation Products Generating Oxidative Stress and Inflammation

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American Journal of Plant Sciences 2024年第3期15卷 193-202页

作者： Ferdinand Kouoh Elombo Erika Van Damme Clara Delepine David Depraetere Ludovic Chaveriat Paul Lunga Keilah Nico Fréderic Njayou Patrick Martin Laboratory of toxicology and pharmacology Department of Biochemistry Faculty of Sciences University of Yaound&#233 I Yaound&#233 Cameroon Dé partement de Chimie IUT B&#233thune Universit&#233 d&#8217Artois B&#233thune France Unité Transformations & Agroressources (ULR7519) Universit&#232 d&#8217Artois-UniLaSalle Bethune France

Vegetable oils are a source of energy, essential fatty acids, antioxidants and fat-soluble vitamins useful for human health care and development. These oils also contribute to organoleptic quality of their products’ derivatives. However, their chemical and physical properties can be modified by the mode of their extraction, storage and distribution. These modifications might negatively affect the nutritional quality of the oils. The goals of this study were to: sample different vegetable oils for cosmetic or dietary use marketed in Cameroon, and verify purity and oxidation states of each kind of oil through determination of its acidity, iodine, peroxide, saponification, refractive indexes and the conformity of the labeling. The carotene content, the level of polar components and specific absorbance were also determined. As the result, six oils namely palm, palm kernel, coconut, black cumin, peanut and shea butter were collected. Apart from labeling, chemicals and physicals parameters analyzed were generally in accordance with the Cameroonian and Codex Alimentarius standard. This study suggests that vegetable oils sampled in the Cameroonian market may not expose consumers to lipid oxidation products generating pathological oxidative stress and inflammation. However, efforts in application of existing standard need to be done as far as labeling are concerned.

关键词： Vegetable Oils Quality Control Labeling Compliance Lipid Oxidation Oxidative Pathology

Interferon-gamma and neuropathy: balance between pain and neuroprotection

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Neural Regeneration Research 2022年第12期17卷 2700-2701页

作者： Valentina Ferrara Alessandra Toti Carla Ghelardini Lorenzo Di Cesare Mannelli Department of Neuroscience PsychologyDrug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology SectionUniversity of FlorenceFlorenceItaly

Chronic pain is sustained by a phenomenon of hyper-activation of nociceptive neurons both at peripheral(peripheral sensitization)and central(central sensitization)levels.The onset and maintenance of pain,however,is to be found in the interaction among the various cell populations in the nervous tissue including neurons and glia(Nam et al.,2016).The pathogenesis of neuropathic pain is extremely complex depending on the primary cause of nerve damage,e.***.traumatic nerve injury is associated with a robust inflammatory response while chemotherapy-induced pain is characterized by a modest phlogistic component(Di Cesare Mannelli et al.,2013).Despite these differences,a powerful common concept to explain the cellular mechanisms underlying pain is the activation of glia.

关键词： pain sustained

The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1761-1780页

作者： Tiecheng Zhong Wenxin Zhang Hongjie Guo Xiaohui Pan Xi Chen Qiaojun He Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Transient receptor potential(TRP)channels are one primary type of calcium(Ca^(2+))permeable channels,and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems.Nowadays,however,accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression,inducing tumor invasion and metastasis.However,the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive.Therefore,in this review,we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance(MDR),metastasis,apoptosis,proliferation,immune surveillance evasion,and the alterations of relevant tumor micro-environment.Moreover,we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors’efficacy.The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented.Furthermore,it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.

关键词： TRP channels Cancer progression Tumor microenvironment Tumor-associated immunocytes Intracellular mechanism Programmed cancer cell death Targeted tumor therapy

Comparing the effects of three decoctions for coronavirus disease 2019 on severe acute respiratory syndrome coronavirus 2-related toll-like receptors-mediated inflammations

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Journal of Traditional Chinese Medicine 2023年第1期43卷 51-59页

作者： LI Ximeng KANG Yuan LI Wenjing LIU Zhuangzhuang XU Zhenlu ZHANG Xiaoyu CAI Runlan GAO Yuan QI Yun Department of pharmacology and toxicology Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100193China

OBJECTIVE:To compare the anti-inflammatory effects of three decoctions for coronavirus disease 2019(COVID-19)[Qingfei Paidu Tang(清肺排毒汤),QF;Huashi Baidu Fang(化湿败毒方),HS;Xuanfei Baidu Fang(宣肺败毒方),XF]in parallelly experimental models by using severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related toll-like receptors(TLRs)ligands and its spike(S)protein as stimulators.METHODS:RAW264.7 macrophages were used to investigate the effects of three decoctions on the inflammations induced by R848,poly(I:C),lipopolysaccharide(LPS),as well as SARS-CoV-2 S protein,in vitro.Mouse endotoxemia model was used for evaluating their anti-inflammatory actions in vivo.The levels of monocyte chemoattractant protein-1(MCP-1),interleukin-6(IL-6),tumor necrosis factorα(TNF-α),and interferon-β(IFN-β)were determined by enzyme-linked immunosorbent assay.RESULTS:Three decoctions could decrease supernatant IL-6,MCP-1,nitric oxide(NO)and TNF-αto varying degrees in activated macrophages.Meanwhile,they did not increase the level of antiviral cytokine IFN-βinduced by TLR3 and TLR4 ligands,but rather suppressed it,suggesting that externally administrated type I interferons(IFN-Is)may be needed for the severe COVID-19 cases characterized by deficient IFN-Is.In mouse endotoxemia model,all three decoctions could suppress serum pro-inflammatory cytokines,but only QF could relieve hypothermia and antagonize diarrhea.CONCLUSIONS:Collectively,our study compared,for the first time,the effects of three decoctions on SARSCoV-2-related TLRs-mediated inflammations.In vitro,three decoctions exert similar suppressive effects on inflammatory cytokines induced by SARS-CoV-2-related TLRs ligands,as well as S protein.In vivo,QF possesses the strongest effects compared with HS and XF.These findings may provide not only experimental basis for the clinical use of three decoctions,but also a rationale for the combination therapy with IFN-Is.

关键词： COVID-19 toll-like receptors inflammation spike glycoprotein coronavirus Qingfei Paidu Huashi Baidu Xuanfei Baidu

Remembering your A, B, C’s: Alzheimer’s disease and ABCA1

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Acta Pharmaceutica Sinica B 2022年第3期12卷 995-1018页

作者： Cutler T.Lewandowski Megan S.Laham Gregory R.J.Thatcher Department of Pharmaceutical Sciences University of Illinois College of PharmacyChicagoIL 60612USA Department of pharmacology and toxicology University of Arizona College of PharmacyTucsonAZ 85721USA

The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.The risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and inflammation.Upregulation of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory signaling.Various strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHR)agonists.These agonists display beneficial preclinical effects;however,important side effects have limited development.In particular,ligands that bind liver X receptor(LXR),the primary NHR that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often observed.The longstanding approach,focusing on LXRβvs.LXRa selectivity,is over-simplistic and has failed.Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.

关键词： Alzheimer’s disease Cardiovascular disease Cholesterol Drug discovery Liver X receptor Nuclear hormone receptor Type 2 diabetes

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1662-1670页

作者： Zhong Li Jimin Xu Yuekun Lang Xiangmeng Wu Saiyang Hu Subodh Kumar Samrat Anil M.Tharappel Lili Kuo David Butler Yongcheng Song Qing-Yu Zhang Jia Zhou Hongmin Li Department of pharmacology and toxicology College of PharmacyTucsonAZ 85721-0207USA Wadsworth Center New York State Department of HealthAlbanyNY 12208USA Chemical Biology Program Department of Pharmacology and ToxicologyUniversity of Texas Medical BranchGalvestonTX 77555USA The Neural Stem Cell Institute RensselaerNY 12144USA Department of pharmacology and Chemical Biology Baylor College of MedicineHoustonTX 77030USA

Zika virus(ZIKV)causes significant human diseases without specific therapy.Previously we found erythrosin B,an FDA-approved food additive,inhibited viral NS2B−NS3 interactions,leading to inhibition of ZIKV infection in cell culture.In this study,we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models.Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model.Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile,mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B,compared to vehicle control.Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions,protease activity and antiviral efficacy.In contrast,introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities,suggesting that the isobenzofuran ring is well tolerated for modifications.Cytotoxicity studies indicated that all derivatives are nontoxic to human cells.Overall,our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.

关键词： Flavivirus Zika virus Dengue virus Antiviral Protease inhibitor Erythrosin B