RESUMO
Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Proteômica , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
(-)-trans-Δ9-Tetrahydrocannabinol (trans-(-)-Δ9-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (trans-(-)-Δ9-THCO) and unnatural Δ9-tetrahydrocannabiorcol (trans-(+)-Δ9-THCO) were successfully synthesized starting from R-limonene and S-limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 µM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural trans-(+)-Δ9-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.
Assuntos
Canabinoides , Neuroblastoma , Humanos , Dronabinol/farmacologia , Limoneno , Neuroblastoma/tratamento farmacológico , Canabinoides/química , Canabinoides/farmacologiaRESUMO
Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo. We found that IIIM-290 induced apoptosis through upregulation of different apoptotic proteins like PUMA, BAX, cytochrome c, cleaved (active) caspase-3, and cleaved PARP in MOLT-4 cells. Moreover, IIIM-290 abated mitochondrial membrane potential, elevated calcium levels, reactive oxygen species, and arrested growth of MOLT-4 cells in the synthesis (S) phase of the cell cycle. Interestingly, the elevation in proapoptotic markers was p53 dependent-the silencing of p53 abrogated apoptosis (programmed cell death) triggered by IIIM-290 in MOLT-4 cells. Furthermore, IIIM-290 significantly enhanced the survival of animals with P388 and L1210 leukemia. Thus, our results put IIIM-290 as a potential candidate for the anticancer lead.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Cromonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piperidinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Cromonas/química , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Piperidinas/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.
Assuntos
Antineoplásicos/farmacologia , Cetonas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/síntese química , Cetonas/química , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/químicaRESUMO
The traditional method of drug discovery process has been surpassed by a rational approach where computer-aided drug designing plays a vital role in the identification of leads from large compound databases. Further, natural products have an important role in drug discovery as these have been the source of most active ingredients of medicines. Herein, in silico structure- and ligand-based approaches have been applied to screen in-house IIIM natural product repository for Akt1 (serine/threonine protein kinases) which is a well-known therapeutic target for cancer due to its overexpression and preventing the cells from undergoing apoptosis. Combined ligand-based and structure-based strategies were applied on to the existing library comprising of about 700 pure natural products, and the compounds identified from screening were biologically evaluated for Akt1 inhibition using Akt1 kinase activity assay. Fourteen promising compounds showed significant inhibition at 500 nM through in vitro screening, and from them, eight were new for Akt1 inhibition. Through the MD studies of Akt1 with the most active compound IN00145, it was inferred that Lys179, Glu191, Glu228, Ala230, Glu234 and Asp292 are the important amino acid residues which provide stability to the Akt1-IN00145 complex. Lead optimization studies were also performed around the actives to design better and selective inhibitors for Akt1. The results emphasized the successful application of virtual screening to identify new Akt1 inhibitor scaffolds that can be developed into a drug candidate in drug discovery programme.
Assuntos
Produtos Biológicos/química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/química , Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Conformação Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Curva ROCRESUMO
Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-6/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Receptor ErbB-2/genética , TrastuzumabRESUMO
A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ. This repositioning of scaffold from PI3Kδ to PI3Kγ isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Reação de Cicloadição , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial-mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial-mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBß (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance.
Assuntos
Neoplasias/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Ativação Enzimática , Humanos , Isoenzimas , Neoplasias/patologia , Transdução de SinaisRESUMO
In the present study, a series of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones were synthesised and evaluated as antiproliferative agents. The compounds were evaluated against a panel of human cancer cell lines. CH-1 exhibited significant cytoxicity against HCT 116 cell lines with an IC50 value of 1.4 and 4.3 µM against "MiaPaCa-2" cell lines. The compound CH-1 was found to induce apoptosis as evidenced by phase contrast microscopy, Hoechst 33258 staining and mitochondrial membrane potential (MMP) loss. The cell phase distribution studies indicated that the apoptotic population increased from 10.22% in the control sample to 57.19% in a sample treated with 20 µM compound CH-1.
Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In this study, we for the first time explored the cellular and molecular mechanism of anticancer properties of fascaplysin, a marine sponge-derived alkaloid. Our study demonstrated that fascaplysin induced a cooperative interaction between apoptotic and autophagic pathways to induce cytotoxicity in HL-60 cells. Fascaplysin treatment not only activated pro-apoptotic events like PARP-1 cleavage and caspase activation but also triggered autophagy signaling as shown by the increased expression of LC3-II, ATG7and beclin. Interestingly, it was found that use of pan-caspase inhibitor completely reversed the fascaplysin mediated cell death as analyzed by MTT and cell cycle assays. It was observed that cell death as well as the expression of pro-death proteins was partially reversed, when key autophagy mediators ATG7 was silenced by siRNA in fascaplysin treated cells. Cooperative involvement of autophagy and apoptotic signaling in cytotoxicity was confirmed when combined silencing of pro-apototic (PARP-1) and autophagic (ATG-7) signaling by respective siRNA's lead to substantial rescue of cell death induced by fascaplysin. Although, apoptosis and autophagy are two independent cell death pathways, our findings provide detailed insight by which both the pathways acted cooperatively to elicit fascaplysin induced cell death in HL-60 cells. Our findings provide molecular insight into the anti-cancer potential of fascaplysin by showing that both autophagic and apoptotic signaling can work together in the induction of cell death.
Assuntos
Autofagia/efeitos dos fármacos , Indóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Células HL-60 , Células HeLa , HumanosRESUMO
BACKGROUND: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells. METHODS: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts. RESULTS: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone. CONCLUSION: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.
Assuntos
Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Triterpenos/química , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/farmacologia , Pirróis/farmacologia , SunitinibeRESUMO
Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.
Assuntos
Antineoplásicos/química , Benzopiranos/química , Carbazóis/química , Paládio/química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Carbazóis/síntese química , Carbazóis/metabolismo , Catálise , Linhagem Celular Tumoral , Colchicina/metabolismo , Humanos , Simulação de Acoplamento Molecular , Multimerização Proteica , Estrutura Quaternária de Proteína , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMO
A series of 4-(N-phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl)quinolines was designed, synthesized and evaluated for their biological potential as anticancer agents by screening the molecules against panel of five human cancer cell lines viz. HL-60, MiaPaCa-2, HCT116, PC-3 and HEP-G2. The series has shown good mTOR inhibitory activity at 0.5 µM concentration. The representative compound 7h was found to be most active with the IC50 of 613 nM against mTOR. In supportive evidence, the western blotting experiment revealed that compound 7h is more potent in inhibiting p-mTOR (S2448) activity in 2-4h at 5 and 10 µM concentrations and was selective and specific towards mTORC1 versus mTORC2. Towards understanding the mechanistic aspects we studied cell cycle analysis, mitochondrial membrane potential loss in MiaPaca-2 cells for compound 7h. The docking study for this series was performed to understand the binding mode of the compounds and its consequent effect in biological activity, the initial interaction studies were found to be useful in design of molecules, where compound 7h has shown additional H-bond interaction with Lys2171 apart from Val2240 and also a small hydrophobic cleft was observed with Leu2185, Met2345 and Ile2356.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Serina-Treonina Quinases TOR/metabolismoRESUMO
INTRODUCTION: Asthma is one of the serious global health problems and cause of huge mortality and morbidity. It is characterized by persistent airway inflammation, airway hyperresponsiveness, increased IgE levels and mucus hypersecretion. Asthma is mediated by dominant Th2 immune response, causing enhanced expression of Th2 cytokines. These cytokines are responsible for the various pathological changes associated with allergic asthma. MATERIALS AND METHODS: The role of Th2 cells in the pathogenesis of the asthma is primarily mediated through the cytokine IL-13, also produced by type 2 innate lymphoid cells, that comes under the transcriptional regulation of GATA3. In this review we will try to explore the link between IL-13 and GATA3 in the progression and regulation of asthma and its possible role as a therapeutic target. CONCLUSION: Inhibition of GATA3 activity or blockade of GATA3 expression may attenuate the interleukin-13 mediated asthma phenotypes. So, GATA3 might be a potential therapeutic target for the treatment of allergic asthma.
Assuntos
Asma/imunologia , Fator de Transcrição GATA3/imunologia , Interleucina-13/imunologia , Animais , Diferenciação Celular , Humanos , Interleucina-13/genética , Células Th2/citologia , Células Th2/imunologiaRESUMO
This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.
Assuntos
Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Cromanos/farmacologia , Lignanas/farmacologia , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Proteína X Associada a bcl-2/genética , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/genética , Proteína 12 Relacionada à Autofagia , Proteína 7 Relacionada à Autofagia , Compostos de Bifenilo/síntese química , Caspases/genética , Caspases/metabolismo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Lignanas/síntese química , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fenóis/síntese química , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/antagonistas & inibidores , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
PI3K/Akt and ERK pathways are important for growth and proliferation of many types of cancers. Therefore, PI3K inhibitor LY294002 (LY) and MEK1/2 inhibitor PD98059 (PD) are used to sensitize many types of cancer cell lines to chemotherapeutic agents, where AKT and ERK pathways are over activated. However, in this study, we show for the first time that PD could protect the leukemia cells independent of ERK pathway inhibition, besides, we also report a detailed mechanism for antiapoptotic effect of LY in HL-60 cells against the cytotoxicity induced by a boswellic acid analog BA145. Apoptosis induced by BA145 is accompanied by downregulation of PI3K/Akt and ERK pathways in human myelogenous leukemia HL-60 cells, having activating N-Ras mutation. Both LY and PD protected the cells against mitochondrial stress caused by BA145, and reduced the release of cytochrome c and consequent activation of caspase-9. LY and PD also diminished the activation of caspase-8 without affecting the death receptors. Besides, LY and PD also reversed the caspase dependent DNA damage induced by BA145. Further studies revealed that LY and PD significantly reversed the inhibitory effect of BA145 on cell cycle regulatory proteins by upregulating hyperphosphorylated retinoblastoma, pRB (S795) and downregulating p21 and cyclin E. More importantly, all these events were reversed by caspase inhibition by Z-VAD-fmk, suggesting that both LY and PD act at the level of caspases to diminish the apoptosis induced by BA145. These results indicate that inhibitors of PI3K/Akt and ERK pathways can play dual role and act against chemotherapeutic agents.
Assuntos
Apoptose/efeitos dos fármacos , Cromonas/farmacologia , Flavonoides/farmacologia , Leucemia/enzimologia , Leucemia/fisiopatologia , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Triterpenos/farmacologia , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Triterpenos/químicaRESUMO
Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).
Assuntos
Transição Epitelial-Mesenquimal , Neoplasias , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias/patologia , Oxirredução , Células-Tronco Neoplásicas/metabolismo , AutofagiaRESUMO
Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.
Assuntos
Apoptose , Neoplasias , Animais , Camundongos , Estresse do Retículo Endoplasmático , Transdução de Sinais , Linhagem Celular Tumoral , Autofagia , Proliferação de CélulasRESUMO
Natural remedies from a range of sources, including plants, animals, microorganisms, and marine life, have made a significant contribution to the treatment of many ailments. Lavender is a Mediterranean shrub from the Lamiaceae family. Lavender flowers (Lavandula flores) include active ingredients (3%), anthocyanins, sugars, phytosterols, minerals, and tannins and are majorly used for herbal applications. Lavender essential oil's descriptive and analytical composition varies depending on genotype, growing region, climatic circumstances, propagation, and morphological characteristics. There are around 300 chemical components in essential oil. Linalool, terpinen-4-ol, linalyl acetate, ocimene, acetate lavandulol, and cineole are the most prominent constituents. Lavender oil has antibacterial and antioxidant properties. The lavender extract helps to prevent dementia and may slow cancer cell growth, while lavender oil is used to treat skin problems. This review will cover the recent medical, economic and regional advancements in levander propagation and how the Council of Scientific & Industrial Research Indian Institute of Integrative (CSIR IIIM) aroma mission is actively acting as a bridge between farmers and their economic improvement by attracting them to the field of medicinal plant cultivation.
RESUMO
Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.