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1.
Braz. j. biol ; 84: e251289, 2024. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1355889

RESUMO

Abstract The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.


Resumo A presente pesquisa foi feita para determinar a capacidade micronuclei e citotóxica do antidepressivo venlafaxina em ensaios agudos e subcrônicos in vivo em camundongos. No primeiro estudo, administramos uma vez 5, 50 e 250 mg/kg do medicamento e incluímos um grupo negativo e um grupo tratado com daunorubicina. As observações foram feitas diariamente durante quatro dias. O ensaio subcrônico durou cinco semanas com administração diária de venlafaxina (1, 5, e 10 mg/kg) mais um grupo negativo e um grupo administrado de imipramina. As observações foram feitas a cada semana. No primeiro ensaio, os resultados não mostraram aumento de eritrócitos policromáticos micronucleados (MNPE), exceto com a dose elevada a 72 h. O efeito citotóxico mais forte foi encontrado com 250 mg/kg a 72 h (um efeito citotóxico de 51% em comparação com o nível médio de controle). No ensaio subcrônico não foi encontrado aumento de MNPE; entretanto, com a dose mais alta, um aumento significativo de eritrócitos normocromáticos micronucleados foi observado nas últimas três semanas (média de 51% em relação ao valor médio de controle). Foi observado um efeito citotóxico com as duas altas doses nas últimas duas semanas (uma diminuição média de 52% em relação ao valor médio de controle dos eritrócitos policromáticos). Os resultados sugerem cautela com a venlafaxina.


Assuntos
Animais , Coelhos , Dano ao DNA , Antineoplásicos , Testes para Micronúcleos , Relação Dose-Resposta a Droga , Eritrócitos , Cloridrato de Venlafaxina/toxicidade
2.
Int J Nanomedicine ; 18: 1219-1243, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36937550

RESUMO

Background: Thalidomide (THD) and its analogues were recently reported as a promising treatment for different types of solid tumors due to their antiangiogenic effect. Methods: In this work, we synthesized a novel THD analogue (TA), and its chemistry was confirmed with different techniques such as IR, mass spectroscopy, elemental analysis as well as 1H and 13C NMR. To increase solubility and anticancer efficacy, a new oil in water (O/W) nanoemulsion (NE) was used in the formulation of the analogue. The novel formula's surface charge, size, stability, FTIR, FE-TEM, in vitro drug release and physical characteristics were investigated. Furthermore, molecular docking studies were conducted to predict the possible binding modes and molecular interactions behind the inhibitory activities of the THD and TA. Results: TA showed a significant cytotoxic activity with IC50 ranging from 0.326 to 43.26 µmol/mL when evaluated against cancerous cells such as MCF-7, HepG2, Caco-2, LNCaP and RKO cell lines. The loaded analogue showed more potential cytotoxicity against MDA-MB-231 and MCF-7-ADR cell lines with IC50 values of 0.0293 and 0.0208 nmol/mL, respectively. Moreover, flow cytometry of cell cycle analysis and apoptosis were performed showing a suppression in the expression levels of TGF-ß, MCL-1, VEGF, TNF-α, STAT3 and IL-6 in the MDA-MB-231 cell line. Conclusion: The novel NE formula dramatically reduced the anticancer dosage of TA from micromolar efficiency to nanomolar efficiency. This indicates that the synthesized analogue exhibited high potency in the NE formulation and proved its efficacy against triple-negative breast cancer cell line.


Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Talidomida/farmacologia , Simulação de Acoplamento Molecular , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos/química , Proliferação de Células , Apoptose
3.
Oncotarget ; 14: 193-206, 2023 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-36913303

RESUMO

Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Humanos , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos/farmacologia , Caspases , Combinação de Medicamentos
5.
Nat Commun ; 14(1): 1394, 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36914633

RESUMO

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Receptor ErbB-2/metabolismo , Citotoxicidade Celular Dependente de Anticorpos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico
6.
Nat Commun ; 14(1): 1359, 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36914652

RESUMO

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.


Assuntos
Antineoplásicos , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico
7.
Sci Rep ; 13(1): 4144, 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36914702

RESUMO

To exploit the advantageous properties of approved drugs to hasten anticancer drug discovery, we designed and synthesized a series of fluoroquinolone (FQ) analogs via functionalization of the acid hydrazides of moxifloxacin, ofloxacin, and ciprofloxacin. Under the NCI-60 Human Tumor Cell Line Screening Assay, (IIIf) was the most potent among moxifloxacin derivatives, whereas (VIb) was the only ofloxacin derivative with significant effects and ciprofloxacin derivatives were devoid of activity. (IIIf) and (VIb) were further selected for five-dose evaluation, where they showed potent growth inhibition with a mean GI50 of 1.78 and 1.45 µM, respectively. (VIb) elicited a more potent effect reaching sub-micromolar level on many cell lines, including MDA-MB-468 and MCF-7 breast cancer cell lines (GI50 = 0.41 and 0.42 µM, respectively), NSCLC cell line HOP-92 (GI50 = 0.50 µM) and CNS cell lines SNB-19 and U-251 (GI50 = 0.51 and 0.61 µM, respectively). (IIIf) and (VIb) arrested MCF-7 cells at G1/S and G1, respectively, and induced apoptosis mainly through the intrinsic pathway as shown by the increased ratio of Bax/Bcl-2 and caspase-9 with a lesser activation of the extrinsic pathway through caspase-8. Both compounds inhibited topoisomerase (Topo) with preferential activity on type II over type I and (VIb) was marginally more potent than (IIIf). Docking study suggests that (IIIf) and (VIb) bind differently to Topo II compared to etoposide. (IIIf) and (VIb) possess high potential for oral absorption, low CNS permeability and low binding to plasma proteins as suggested by in silico ADME calculations. Collectively, (IIIf) and (VIb) represent excellent lead molecules for the development of cytotoxic agents from quinolone scaffolds.


Assuntos
Antineoplásicos , Fluoroquinolonas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Fluoroquinolonas/farmacologia , Moxifloxacina/farmacologia , Proliferação de Células , Pontos de Checagem do Ciclo Celular , Antineoplásicos/química , Linhagem Celular Tumoral , Ciprofloxacina/farmacologia , Apoptose , Ofloxacino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ciclo Celular
8.
J Zhejiang Univ Sci B ; 24(3): 207-220, 2023 Mar 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36915997

RESUMO

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.


Assuntos
Alcoolismo , Antineoplásicos , Anemia de Fanconi , Síndrome de Abstinência a Substâncias , Neoplasias Testiculares , Feminino , Masculino , Humanos , Cisplatino/farmacologia , Dissulfiram/farmacologia , Neoplasias Testiculares/tratamento farmacológico , Anemia de Fanconi/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células
9.
J Nanobiotechnology ; 21(1): 89, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36918874

RESUMO

Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal-organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Biomimética , Neoplasias Hepáticas/patologia , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Microambiente Tumoral
10.
J Med Chem ; 66(5): 3393-3410, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36891739

RESUMO

A series of autophagy-targeted antimetastatic clioquinol (CLQ) platinum(IV) conjugates were designed and prepared by incorporating an autophagy activator CLQ into the platinum(IV) system. Complex 5 with the cisplatin core bearing dual CLQ ligands with potent antitumor properties was screened out as a candidate. More importantly, it displayed potent antimetastatic properties both in vitro and in vivo as expected. Mechanism investigation manifested that complex 5 induced serious DNA damage to increase γ-H2AX and P53 expression and caused mitochondria-mediated apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it promoted prodeath autophagy by suppressing PI3K/AKT/mTOR signaling and activating the HIF-1α/Beclin1 pathway. The T-cell immunity was elevated by restraining the PD-L1 expression and subsequently increasing CD3+ and CD8+ T cells. Ultimately, metastasis of tumor cells was suppressed by the synergistic effects of DNA damage, autophagy promotion, and immune activation aroused by CLQ platinum(IV) complexes. Key proteins VEGFA, MMP-9, and CD34 tightly associated with angiogenesis and metastasis were downregulated.


Assuntos
Antineoplásicos , Clioquinol , Platina/farmacologia , Clioquinol/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Autofagia , Linhagem Celular Tumoral
11.
PLoS One ; 18(3): e0282586, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36893122

RESUMO

A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 µM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 µM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).


Assuntos
Antineoplásicos , Teobromina , Teobromina/farmacologia , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/farmacologia , Antineoplásicos/química , Descoberta de Drogas , Receptores ErbB/metabolismo , Relação Estrutura-Atividade , Proliferação de Células , Inibidores de Proteínas Quinases/química
12.
Nat Commun ; 14(1): 1290, 2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36894562

RESUMO

Acquired chemoresistance to proteasome inhibitors is a major obstacle in managing multiple myeloma but key regulators and underlying mechanisms still remain to be explored. We find that high level of HP1γ is associated with low acetylation modification in the bortezomib-resistant myeloma cells using SILAC-based acetyl-proteomics assay, and higher HP1γ level is positively correlated with poorer outcomes in the clinic. Mechanistically, elevated HDAC1 in the bortezomib-resistant myeloma cells deacetylates HP1γ at lysine 5 and consequently alleviates the ubiquitin-mediated protein degradation, as well as the aberrant DNA repair capacity. HP1γ interacts with the MDC1 to induce DNA repair, and simultaneously the deacetylation modification and the interaction with MDC1 enhance the nuclear condensation of HP1γ protein and the chromatin accessibility of its target genes governing sensitivity to proteasome inhibitors, such as CD40, FOS and JUN. Thus, targeting HP1γ stability by using HDAC1 inhibitor re-sensitizes bortezomib-resistant myeloma cells to proteasome inhibitors treatment in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in inducing drug resistance to proteasome inhibitors of myeloma cells and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in refractory or relapsed multiple myeloma patients.


Assuntos
Antineoplásicos , Mieloma Múltiplo , Humanos , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Inibidores de Proteassoma/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Fatores de Transcrição/farmacologia , Antineoplásicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo
13.
Int J Nanomedicine ; 18: 1195-1218, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36926681

RESUMO

Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Nanomedicina , Sistemas de Liberação de Fármacos por Nanopartículas , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Lipossomos/farmacologia , Microambiente Tumoral
14.
Gan To Kagaku Ryoho ; 50(3): 321-325, 2023 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-36927900

RESUMO

We evaluated the efficacy and safety of the RV21-01 scalp cooling device in controlling hair loss during chemotherapy in this study. Thirty-nine breast cancer patients who underwent anthracycline- and/or taxane-based chemotherapy were assigned to the scalp cooling group(27 patients)and the hair loss observation group(12 patients). The alopecia rate using the NCI alopecia toxicity criteria and the quantitative alopecia toxicity grade was 51.9%(14/27 patients)and 100%(12/12 patients)in the scalp cooling and hair loss observation groups, respectively. Regarding safety, all subjects in both the scalp cooling and hair loss observation groups experienced adverse events; only 1 subject in each group experienced a severe adverse event due to chemotherapy and majority of the subjects in both groups experienced minor adverse events. RV21-01 scalp cooling therapy was demonstrated to be effective in reducing hair loss in patients undergoing standard chemotherapy for breast cancer. In addition, the adverse events associated with the scalp cooling therapy were minor and mild, and hence, deemed acceptable.


Assuntos
Antineoplásicos , Neoplasias da Mama , Hipotermia Induzida , Humanos , Feminino , Neoplasias da Mama/complicações , Couro Cabeludo , Alopecia/induzido quimicamente , Alopecia/prevenção & controle , Alopecia/tratamento farmacológico , Hipotermia Induzida/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos/efeitos adversos
15.
ACS Appl Mater Interfaces ; 15(10): 13460-13471, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36867432

RESUMO

Conventional cancer therapy methods have serious drawbacks that are related to the nonspecific action of anticancer drugs that leads to high toxicity on normal cells and increases the risk of cancer recurrence. The therapeutic effect can be significantly enhanced when various treatment modalities are implemented. Here, we demonstrate that the radio- and photothermal therapy (PTT) delivered through nanocarriers (gold nanorods, Au NRs) in combination with chemotherapy in a melanoma cancer results in complete tumor inhibition compared to the single therapy. The synthesized nanocarriers can be effectively labeled with 188Re therapeutic radionuclide with a high radiolabeling efficiency (94-98%) and radiochemical stability (>95%) that are appropriate for radionuclide therapy. Further, 188Re-Au NRs, mediating the conversion of laser radiation into heat, were intratumorally injected and PTT was applied. Upon the irradiation of a near-infrared laser, dual photothermal and radionuclide therapy was achieved. Additionally, the combination of 188Re-labeled Au NRs with paclitaxel (PTX) has significantly improved the treatment efficiency (188Re-labeled Au NRs, laser irradiation, and PTX) compared to therapy in monoregime. Thus, this local triple-combination therapy can be a step toward the clinical translation of Au NRs for use in cancer treatment.


Assuntos
Antineoplásicos , Melanoma , Nanotubos , Humanos , Terapia Fototérmica , Antineoplásicos/farmacologia , Fototerapia/métodos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Melanoma/tratamento farmacológico , Radioisótopos/uso terapêutico , Ouro/farmacologia , Linhagem Celular Tumoral
16.
Endocrinol Diabetes Nutr (Engl Ed) ; 70(2): 136-150, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36868926

RESUMO

INTRODUCTION: The cause of death can be attributed to malnutrition in 10-20% of cancer patients. Patients with sarcopenia present more chemotherapy toxicity, less progression-free time, less functional capacity and more surgical complications. Antineoplastic treatments have a high prevalence of adverse effects that compromise nutritional status. The new chemotherapy agents present direct toxicity on the digestive tract (nausea, vomiting, diarrhoea and/or mucositis). We present the frequency of adverse effects with nutritional impact of the most frequent chemotherapy agents used in the treatment of solid tumours, as well as strategies for early diagnosis and nutritional treatment. MATERIAL AND METHODS: Review of commonly used cancer treatments (cytotoxic agents, immunotherapy, targeted therapies) in colorectal, liver, pancreatic; lung, melanoma, bladder, ovary, prostate and kidney cancer. The frequency (%) of gastrointestinal effects, and those of grade ≥3 are recorded. A systematic bibliographic search was carried out in PubMed, Embase, UpToDate, international guides and technical data sheets. RESULTS: They are shown in the form of tables in which the drugs appear together with the probability that they present any digestive adverse effect and the percentage of serious adverse effects (Grade ≥ 3). DISCUSSION: Antineoplastic drugs are associated with a high frequency of digestive complications with nutritional repercussions, which can reduce QoL and cause death as a result of malnutrition or due to the limiting effect of suboptimal treatments, closing the malnutrition-toxicity loop. It is necessary to inform the patient about the risks and establish local protocols regarding the use of antidiarrheal drugs, antiemetics and adjuvants in the management of mucositis. We propose action algorithms and dietary advice that can be used directly in clinical practice, to prevent the negative consequences of malnutrition.


Assuntos
Antineoplásicos , Desnutrição , Mucosite , Neoplasias , Masculino , Feminino , Humanos , Estado Nutricional , Mucosite/induzido quimicamente , Mucosite/complicações , Qualidade de Vida , Antineoplásicos/efeitos adversos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Desnutrição/complicações
17.
Sci Transl Med ; 15(687): eabn2110, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36921036

RESUMO

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.


Assuntos
Antineoplásicos , Pancreatite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Camundongos , Asparaginase/efeitos adversos , Retinoides/efeitos adversos , Vitamina A/uso terapêutico , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Análise de Sistemas , Antineoplásicos/efeitos adversos
18.
Chin Clin Oncol ; 12(1): 5, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36922354

RESUMO

BACKGROUND AND OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is a rare hepatic malignancy with poor prognosis, which has seen an increased incidence over the last decade. Most patients present with advanced disease that is not amenable to surgical resection, and those who are able to undergo resection, frequently develop recurrent disease. With the rise of precision medicine, several targetable mutations have been described for iCCA and are currently under investigations. The development of improved targeted therapies is critical to prolonged overall survival (OS), and the use of targeted agents for iCCA is currently the focus of several ongoing randomized controlled trials. The objective of this review is to summarize current guidelines for diagnosis, surgical resection, and systemic treatment, which includes ongoing clinical trials investigated targeted therapies. METHODS: A comprehensive review was performed using MEDLINE/PubMed with the end search date of October 1, 2022. In PubMed the terms "intrahepatic cholangiocarcinoma," "bile duct cancer", "targeted therapies", and "clinical trials" were searched. KEY CONTENT AND FINDINGS: The mainstay of treatment for iCCA is R0 resection with lymphadenectomy. Following surgical resection, new guidelines recommend 6 months of adjuvant capecitabine. Among patients with advanced or metastatic disease, systemic chemotherapy plays a significant role in prolonging survival for these patients. CONCLUSIONS: Surgical resection represents the mainstay of treatment followed by 6 months of adjuvant capecitabine. While additional data is needed through randomized controlled trials, targeted therapies including fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), and erythroblastic oncogene B2 (ErbB2) inhibitors offer promising results as adjuncts to current standard of care in iCCA, particularly among individuals with unresectable disease. Future recommendations regarding the use of targeted therapy will emerge as clinical trial data become available.


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Capecitabina/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/diagnóstico
19.
PeerJ ; 11: e15049, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36923503

RESUMO

Background: Menthol, a natural compound in peppermint leaves, has several biological activities, including antioxidant, anti-inflammatory, antiviral, antibacterial and anticancer properties. This study revealed the anti-leukemic effects and its underlying mechanisms of the menthol related apoptosis signaling pathway and autophagy in both NB4 and Molt-4 leukemic cell lines. Methods: Both leukemic cells were treated with menthol in various concentration. Cell viability was assessed using MTT assay, whereas apoptosis and autophagy were analyzed by flow cytometry using Annexin V-FITC/PI and anti-LC3/FITC antibodies staining, respectively. Apoptotic and autophagic related gene and protein expression were detected using RT-qPCR and western blot analysis, respectively. Moreover, STITCH database was used to predicts the interaction between menthol and proposed proteins. Results: Menthol significantly decreased cell viability in NB4 and Molt-4 cell lines in dose dependent manner. In combination of menthol and daunorubicin, synergistic cytotoxic effects were observed in leukemic cells. However, there was a minimal effect found on normal, peripheral blood mononuclear cells (PBMCs). Moreover, menthol significantly induced apoptosis induction via upregulation of caspase-3, BAX, p53 and downregulation of MDM2 mRNA expression. Autophagy was also induced by menthol through upregulating ATG3 and downregulating mTOR mRNA expression. For protein expression, menthol significantly increased caspase-3 whereas decreased mTOR in both leukemic cells. Conclusions. These results suggest that menthol exhibits cytotoxic activities by inhibition of cell proliferation, induction of apoptosis and autophagy through activating the caspase cascade, altering BAX and p53/MDM2, and regulating autophagy via the ATG3/mTOR signaling pathway.


Assuntos
Antineoplásicos , Mentol , Caspase 3/metabolismo , Mentol/farmacologia , Mentha piperita/genética , Linhagem Celular Tumoral , Proteína X Associada a bcl-2/metabolismo , Leucócitos Mononucleares/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Antineoplásicos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Autofagia , RNA Mensageiro/farmacologia
20.
Theranostics ; 13(4): 1443-1453, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36923532

RESUMO

Background: Chromothripsis caused massive, clustered genomic rearrangements is prevalent in cancer and is considered a new paradigm for tumorigenesis and progression. In this study, we investigated the association among chromothripsis, anti-tumor immune responses, and responsiveness to immune checkpoint blockade (ICB). Methods: Quantification of immune cell infiltration and functional enrichment of immune-related signaling pathways were performed in the discovery set (n = 9403) and the validation set (n = 1140). we investigated the association between chromothripsis and anti-tumor immune responses. In the immunotherapy cohort, copy number alteration-based chromothripsis scores (CPSs) were introduced to assess the extent of chromothripsis to evaluate its association with responsiveness to ICB. Results: In the discovery set and the validation set, the ratios of CD8+ T cells to Tregs, TAMs, and MDSCs were significantly lower in tumors with chromothripsis (P = 1.5 × 10-13, P = 5.4 × 10-8, and P = 1.2 × 10-4, respectively, TCGA; P = 1.0 × 10-13, P = 3.6 × 10-15, and P = 3.3 × 10-3, respectively, PCAWG). The relevant pathways underlying the antitumor immune effect were significantly enriched in tumors without chromothripsis. Chromothripsis can be used as an independent predictor, and patients with low-CPSs experienced longer overall survival (OS) after immunotherapy [HR, 1.90; 95% confidence interval, 1.10-3.28; P = 0.019]. Conclusions: Our findings highlight the reduced cytotoxic immune infiltration in tumors with chromothripsis and enhanced immunosuppression in the tumor microenvironment. Chromothripsis can thus be used as a potential indicator to help identify patients who will respond to ICB, which could complement established biomarkers.


Assuntos
Antineoplásicos , Cromotripsia , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Imunoterapia , Microambiente Tumoral
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