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1.
Anticancer Res ; 41(10): 4807-4820, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593430

RESUMO

BACKGROUND/AIM: LY2835219 (LY), a novel CDK4/6 inhibitor, prevents cell proliferation through G1 arrest. Docetaxel (DTX) and paclitaxel (PTX) are cytotoxic drugs targeting tubulin-mediated apoptotic cell death via G2/M arrest. We evaluated the antitumor effects of DTX/PTX and LY individually and in combination in lung adenocarcinoma cells with or without KRAS mutations and xenograft mice harboring KRAS mutations. MATERIALS AND METHODS: We investigated in vitro/in vivo changes in signaling molecules and analyzed cell proliferation, cycle, and apoptosis via flow cytometry and western blotting. RESULTS: LY cytotoxicity was dose-dependent and varied with KRAS mutation status. DTX→LY showed synergistic cytotoxicity regardless of KRAS mutation. Furthermore, the synergistic effect of PTX→LY was significantly greater than that of PTX+LY. DTX→LY remarkably reduced the number of G0/G1 cells and increased the number of G2/M arrested cells, resulting in an increase in apoptosis and subG1 cells. CONCLUSION: DTX→LY has synergistic antitumor effect in lung cancer cells and xenograft mice regardless of KRAS mutation.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Taxoides/farmacologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Pharm ; 607: 121017, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34416334

RESUMO

Drug resistance remains a major challenge in achieving cures in cancer patients. Cabazitaxel has shown the ability to overcome drug resistance induced by paclitaxel and docetaxel; however, substantially high toxicity has been observed in patients receiving this agent, which compromises its efficacy. We have previously demonstrated that a polymeric platform (termed cabazitaxel-NPs) encapsulating the oligolactide-cabazitaxel conjugate exhibits desired antitumor efficacy and improved in vivo tolerability. However, we found that upon cabazitaxel treatment, cancer cells adapted to activate Akt signaling, which potentially discounts the drug efficacy. We therefore hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically sensitize the resistant cancer. In this study, we confirmed that nanoparticle formulation reduced the systemic toxicity, with higher tolerance than solution-based free cabazitaxel agent in animals. Interestingly, the activation of Akt signaling in the resistant cancer was reversed by the addition of MK-2206. In particular, the collaboration of these two ingredients was demonstrated to maximize the efficacy in vitro and in a xenograft model bearing paclitaxel-resistant tumors. Mechanistically, Akt inhibition increased the microtubule-stabilizing effect of cabazitaxel nanomedicine. Collectively, this report introduced a binary platform composed of cytotoxic nanotherapeutics and inhibitors with certain targets to combat multidrug resistance, and such a combined regimen has the potential for the clinical treatment of patients with resistant cancer.


Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Nanomedicina , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Taxoides/farmacologia
3.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279417

RESUMO

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds ß-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Esteroides/farmacologia , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micrometástase de Neoplasia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 41(8): 3753-3758, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281834

RESUMO

BACKGROUND/AIM: Cabazitaxel is known to be effective in patients with castration-resistant prostate cancer (CRPC) showing resistance to docetaxel. The objective of this study was to investigate the molecular mechanism mediating cytotoxic activity of cabazitaxel in docetaxel-resistant human CRPC cells. MATERIALS AND METHODS: Parental human CRPC cell line PC3 (PC3/P) was continuously exposed to increasing doses of docetaxel, and a cell line resistant to docetaxel, PC3/R, was developed. Phenotypic differences between these cell lines were investigated. RESULTS: There were no significant differences in sensitivity to cabazitaxel between PC3/P and PC3/R. In PC3/P, both docetaxel and cabazitaxel markedly inhibited the phosphorylation of AKT serine/threonine kinase 1 (AKT) and p44/42 mitogen-activated protein kinase (MAPK). In PC3/R, however, phosphorylation of AKT and p44/42 MAPK were maintained following treatment with docetaxel, whereas treatment with cabazitaxel resulted in the marked down-regulation of phosphorylation of AKT but not that of p44/42 MAPK. Furthermore, additional treatment of PC3/R with a specific inhibitor of AKT significantly enhanced the cytotoxic activity of docetaxel but not that of cabazitaxel. Growth of PC3/R in nude mice after treatment with cabazitaxel was significantly inhibited compared with that after treatment with docetaxel. CONCLUSION: Antitumor activity of cabazitaxel in docetaxel-resistant CRPC cells was explained, at least in part, by the inactivation of persistently phosphorylated AKT even after treatment with docetaxel.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Animais , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Morfolinas/farmacologia , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Acta Biomater ; 130: 409-422, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087447

RESUMO

Chemotherapy has been widely used for treating the vast majority of cancer patients. Unfortunately, only a fraction of patients can respond to chemotherapies, but these patients still experience severe side effects. In this context, a wide range of nanotherapeutic platforms have been developed with the aim of improving treatment outcomes while reducing drug toxicities. Nanohydrogels are highly appealing "smart" biocompatible and biodegradable vehicles for either local or systemic delivery of bioactive compounds. Here, we developed prodrug hydrogelators that can undergo one-step distillation-precipitation polymerization to form systemically injectable nanohydrogels. The optimized nanohydrogels were capable of rapidly releasing active agents (e.g., the cytotoxic agent cabazitaxel or the PI3K molecular inhibitor PI103) in response to the reducing tumor microenvironment, while drug release was very slow in the absence of the reductive reagent glutathione. Cabazitaxel-loaded nanogels showed preferential tumor accumulation, and administration of nanogels produced durable tumor regression in a docetaxel-resistant cervical tumor xenograft-bearing mouse model. More significantly, nanogel-based therapy was proven to demonstrate a higher safety profile than solution-based free cabazitaxel. Collectively, this study provides an alternative formulation that meets the essential requirements of high stability in the blood, spontaneous drug release at diseased sites, favorable safety in vivo, and translational capacity for further investigations. STATEMENT OF SIGNIFICANCE: Chemotherapy remains a considerable challenge and only a fraction of patients can respond to chemotherapies. Here we report an intratumoral reducing agent-activatable, tumor-targeting prodrug nanogel platform for therapeutic delivery. To this end, two anticancer agents (e.g., cytotoxic cabazitaxel or PI3K molecular inhibitor PI103) are tested. Prodrug nanogels are stable in the blood but performed reduction-triggered release of chemically unmodified drug molecules in cancerous tissues. Cabazitaxel-loaded nanogels exhibit satisfactory anticancer performance in a preclinical docetaxel-resistant tumor model. This is a practical and expedient approach that combines the prodrug strategy and nanogel scaffold to re-engineer a hydrophobic and toxic anticancer drug. The approach also is broadly applicable for the formulation of other agents to improve the therapeutic index.


Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Ativação Metabólica , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Taxoides/farmacologia , Taxoides/uso terapêutico , Microambiente Tumoral
6.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068627

RESUMO

α-Trifluoromethyl chalcones were prepared and evaluated for their antiproliferative activities against androgen-independent prostate cancer cell lines as well as five additional types of human tumor cell lines. The most potent chalcone 5 showed superior antitumor activity in vivo with both oral and intraperitoneal administration at 3 mg/kg. Cell-based mechanism of action studies demonstrated that 5 induced cell accumulation at sub-G1 and G2/M phases without interfering with microtubule polymerization. Furthermore, several cancer cell growth-related proteins were identified by using chalcone 5 as a bait for the affinity purification of binding proteins.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Docetaxel/farmacologia , Humanos , Masculino , Camundongos SCID , Taxoides/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Acc Chem Res ; 54(10): 2347-2360, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33942612

RESUMO

The taxane diterpenes are a pharmaceutically vital family of natural products, consisting of more than 550 congeners. All taxane diterpenes are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as "yews" and have a history of over 50 years as potent anticancer compounds. The most prominent congener, taxol (paclitaxel = PTX), has been used in clinics for more than 25 years and is one of the top-selling anticancer drugs worldwide, with annual sales reaching 1.5 billion USD in 1999. Within the taxane diterpene family 11 different scaffolds originating from rearrangements, fragmentations, or transannular C-C bond formations of the "classical taxane core" are known. Among them, five different scaffolds alone belong to the so-called complex or cyclotaxane subfamily, their signature structural feature bearing different types and numbers of transannular C-C bonds across the classical taxane backbone. For synthetic chemists, these five scaffolds represent by far the most challenging of all and have thus evaded total synthesis as well as detailed pharmaceutical evaluation-the latter due to extremely poor sourcing from natural producers. The cousinship of complex taxanes to taxol renders them potentially interesting compounds for drug research in the fight against cancer.This Account specifically summarizes the work on nonclassical taxanes from a biosynthetic, as well as a synthetic, point and provides a synthetic perspective on complex taxanes. Special attention is given to the biosynthetic relationship of complex taxanes and their biological emergence from classical taxanes. The transannular C-C bond forming events in the biosynthesis leading to the five individual scaffolds within this subfamily are structured on the basis of the exact type and number of these specific C-C bond formations. Since functionalization of the classical taxane core in the "oxidase phase" of the biosynthesis precedes the formation of complex taxanes, and is in part prerequisite for these transannular cyclization events, a detailed discussion of these oxidations of the classical taxane backbone is provided. Synthetic efforts toward nonclassical taxanes are scarce in literature and are thus presented in a comprehensive manner for abeotaxanes and complex taxanes. The last part of this Account deals with a synthetic perspective on the synthesis of complex taxanes (cyclotaxanes) and how these most intricate scaffolds can potentially be obtained via a deconvolution strategy. This discussion involves in part unpublished results by our group and is based upon synthetic studies in the literature. The deconvolution strategy we advocate aims for selective fragmentations of the signature transannular C-C bonds of the most intricate scaffold represented by the natural product canataxpropellane, which has recently been synthesized by our group. This strategy represents the converse process of the biosynthesis of complex taxanes (e.g., transannular cyclizations) and is enabled and feasible due to our approach to the canataxpropellane scaffold. We show that, by following this deconvolution strategy, all five scaffolds of complex taxanes can thereby be accessed.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Taxoides/farmacologia , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Humanos , Neoplasias/patologia , Taxoides/química
8.
Carbohydr Polym ; 264: 118000, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33910734

RESUMO

The safe and effective drug delivery system is important for cancer therapy. Here in, we first constructed a delivery system Cabazitaxel(Cab)@MPN/CS between metal-polyphenol (MPN) and chitosan (CS) to deliver Cab for melanoma therapy. The preparation process is simple, green, and controllable. After introducing CS coating, the drug loading was improved from 7.56 % to 9.28 %. Cab@MPN/CS NPs released Cab continuously under acid tumor microenvironment. The zeta potential of Cab@MPN/CS NPs could be controlled by changing the ratio of Cab@MPN and CS solutions. The positively charged Cab@MPN/CS accelerate B16F10 cell internalization. After internalized, Cab@MPN/CS NPs could escape from lysosomes via the proton sponge effect. The permeability of CS promotes the penetration of Cab@MPN/CS to the deeper B16F10 tumor spheroids. In vivo results showed that Cab@MPN/CS NPs have a longer retention time in tumor tissues and significantly inhibit tumor growth by up-regulating TUNEL expression and down-regulating KI67 and CD31 expression. Thus, this delivery system provides a promising strategy for the tumor therapy in clinic.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Melanoma/tratamento farmacológico , Nanopartículas Metálicas/química , Polifenóis/química , Taxoides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Antígeno Ki-67/metabolismo , Melanoma/metabolismo , Camundongos , Tamanho da Partícula , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Taxoides/química , Microambiente Tumoral/efeitos dos fármacos
9.
Theranostics ; 11(12): 6019-6032, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897896

RESUMO

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro. Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.


Assuntos
Clorofila/análogos & derivados , Nanopartículas/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Clorofila/farmacologia , Dimerização , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Fotoquimioterapia/métodos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Taxoides/farmacologia , Distribuição Tecidual
10.
Theranostics ; 11(12): 5713-5727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897877

RESUMO

New strategies to fabricate nanomedicines with high translational capacity are urgently desired. Herein, a new class of self-assembled drug cocktails that addresses the multiple challenges of manufacturing clinically useful cancer nanomedicines was reported. Methods: With the aid of a molecular targeted agent, dasatinib (DAS), cytotoxic cabazitaxel (CTX) forms nanoassemblies (CD NAs) through one-pot process, with nearly quantitative entrapment efficiency and ultrahigh drug loading of up to 100%. Results: Surprisingly, self-assembled CD NAs show aggregation-induced emission, enabling particle trafficking and drug release in living cells. In preclinical models of human cancer, including a patient-derived melanoma xenograft, CD NAs demonstrated striking therapeutic synergy to produce a durable recession in tumor growth. Impressively, CD NAs alleviated the toxicity of the parent CTX agent and showed negligible immunotoxicity in animals. Conclusions: Overall, this approach does not require any carrier matrices, offering a scalable and cost-effective methodology to create a new generation of nanomedicines for the safe and efficient delivery of drug combinations.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Camundongos , Nanomedicina/métodos , Taxoides/farmacologia
11.
BMC Cancer ; 21(1): 360, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827483

RESUMO

BACKGROUND: The rate of toxic deaths related to induction chemotherapy in the treatment of locally advanced head and neck cancers is unacceptable and calls into question this therapeutic strategy, which is however highly effective in terms of rate and speed of response. The purpose of the study was to investigate predictive factors of toxicity of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced head and neck cancers (LAHNC). METHODS: Between June 2009 and December 2017, 113 patients treated consecutively with TPF were included retrospectively. Patients were receiving induction chemotherapy for either an inoperable cancer or laryngeal preservation. For inoperable cancer, induction chemotherapy was proposed to patients presenting either a large tumor with strong symptoms (dyspnea, dysphagia, pain) or a tumor with rapid progression. Risk factors were chosen among the initial patient and tumour characteristics and chemotherapy modalities. RESULTS: Eighty-nine patients (79%) were male; the median age was 58 years [32-71]. Sixty-nine (61%) patients were treated for inoperable cancer and 44 (39%) for laryngeal preservation. 45% had stage IVa cancer, 28% stage III and 25% stage IVb. Sixty percent of patients had a partial response after TPF, 22% had a complete response, 12% were stable, 5% were progressing, and 1% had a discordant response. Thirty-four patients (30%) received enteral feeding during induction chemotherapy with TPF. The possibility of oral feeding without a tube was predictive of a better response (p = 0.003). Seven (6%) patients died during TPF. There was an increased risk of death with preexisting liver dysfunction (liver dysmorphia on imaging or decrease prothrombin rate) (p = 0.032). There was an increased risk of grade ≥ 3 infection if an enteral feeding occurred during the period of induction chemotherapy (p = 0.03). CONCLUSIONS: TPF induction chemotherapy had an 82% objective response rate with 6% toxic deaths. Nutritional status and the presence of hepatic dysfunction are significant risk factors to be taken into account in therapeutic decisions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quimioterapia de Indução/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Taxoides/farmacologia , Taxoides/uso terapêutico
12.
J Biochem ; 170(1): 89-96, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33729485

RESUMO

Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Cabazitaxel, a second-generation taxane, has been used for the CRPC treatment, but its tolerance is an urgent problem to be solved. In this study, to elucidate the acquisition mechanism of the cabazitaxel-resistance, we established cabazitaxel-resistant prostate cancer 22Rv1 (Cab-R) cells, which exhibited ∼sevenfold higher LD50 against cabazitaxel than the parental 22Rv1 cells. Cab-R cells showed marked increases in nuclear accumulation of NF-E2 related factor 2 (Nrf2) and expression of Nrf2-inducible antioxidant enzymes compared to 22Rv1 cells, suggesting that Nrf2 signalling is homeostatically activated in Cab-R cells. The cabazitaxel sensitivity of Cab-R cells was enhanced by silencing of Nrf2, and that of 22Rv1 cells was reduced by activation of Nrf2. Halofuginone (HF) has been recently identified as a potent Nrf2 synthetic inhibitor, and its treatment of Cab-R cells not only suppressed the Nrf2 signalling by decreasing both nuclear and cytosolic Nrf2 protein levels, but also significantly augmented the cabazitaxel sensitivity. Thus, inhibition of Nrf2 signalling may be effective in overcoming the cabazitaxel resistance in prostate cancer cells.


Assuntos
Antineoplásicos Hormonais/farmacologia , Antioxidantes/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
13.
Theranostics ; 11(9): 4137-4154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754053

RESUMO

Rationale: Prodrug strategies that render the drug temporarily inactive through a cleavable linkage are able to modulate the physicochemical properties of drugs for adaptive nanoparticle (NP) formulation. Here we used cabazitaxel as a model compound to test the validity of our "balancing NP stability and specific drug activation" strategy. Methods: Cabazitaxel is conjugated to hydrophobic polylactide fragments with varying chain lengths via a self-immolation linkage, yielding polymeric prodrugs that can be reactivated by reductive agents in cells. Following a nanoprecipitation protocol, cabazitaxel prodrugs can be stably entrapped in amphiphilic polyethylene-block-polylactide matrices to form core-shell nanotherapies with augmented colloidal stability. Results: Upon cellular uptake followed by intracellular reduction, the NPs spontaneously release chemically unmodified cabazitaxel and exert high cytotoxicity. Studies with near-infrared dye-labeled NPs demonstrate that the nanodelivery of the prodrugs extends their systemic circulation, accompanied with increased drug concentrations at target tumor sites. In preclinical mouse xenograft models, including two paclitaxel-resistant xenograft models, the nanotherapy shows a remarkably higher efficacy in tumor suppression and an improved safety profile than free cabazitaxel. Conclusion: Collectively, our approach enables more effective and less toxic delivery of the cabazitaxel drug, which could be a new generalizable strategy for re-engineering other toxic and water-insoluble therapeutics.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Poliésteres/química , Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Taxoides/química , Taxoides/farmacologia
14.
PLoS One ; 16(3): e0246733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661931

RESUMO

Three-dimensional spheroid cultures have been shown to better physiologically mimic the cell-cell and cell-matrix interactions that occur in solid tumors more than traditional 2D cell cultures. One challenge in spheroid production is forming and maintaining spheroids of uniform size. Here, we developed uniform, high-throughput, multicellular spheroids that self-assemble using microwell plates. DU145 and PC3 cells were cultured as 2D monolayers and 3D spheroids to compare sensitization of TRAIL-resistance cancer cells to TRAIL mediated apoptosis via chemotherapy based on dimensionality. Monocultured monolayers and spheroids were treated with soluble TRAIL alone (24 hr), DTX or CBZ alone (24 hr), or a combination of taxane and TRAIL (24 + 24 hr) to determine the effectiveness of taxanes as TRAIL sensitizers. Upon treatment with soluble TRAIL or taxanes solely, monolayer cells and spheroids exhibited no significant reduction in cell viability compared to the control, indicating that both cell lines are resistant to TRAIL and taxane alone in 2D and 3D. Pretreatment with CBZ or DTX followed by TRAIL synergistically amplified apoptosis in 2D and 3D DU145 cell cultures. PC3 spheroids were more resistant to the combination therapy, displaying a more additive effect in the DTX + TRAIL group compared to 2D. There was a downregulation of DR4/5 expression in spheroid form compared to monolayers in each cell line. Additionally, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were cocultured with both PCa cell lines as spheroids to determine if CAFs confer additional resistance to chemotherapy. We determined that co-cultured spheroids show similar drug resistance to monocultured spheroids when treated with taxane plus TRAIL treatment. Collectively, these findings suggest how the third dimension and cocultures of different cell types effect the sensitization of androgen-independent prostate cancer cells to TRAIL, suggesting therapeutic targets that could overcome TRAIL-resistance in metastatic castration-resistant prostate cancer (mCRPC).


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Taxoides/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino
15.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673002

RESUMO

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes-first-line treatments-turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimerização/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Taxoides/uso terapêutico , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêutico
16.
Chem Commun (Camb) ; 57(18): 2261-2264, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33532809

RESUMO

Using hydrophobic cabazitaxel as a target anticancer drug, we show that the conjugation of oligo(ethylene glycol)-oligolactide (OEG-OLA) via a self-immolative linkage induces the self-assembly of the resulting prodrug into injectable nanoparticles. The nanoparticles release chemically unmodified cabazitaxel after endocytosis in cancer cells. With the optimal conjugate, the nanotherapy not only potently induces tumor regression but also has a higher safety margin in animals than the free drug administered in its clinical formulation. Our studies highlight the design rationale that attaching a short amphiphilic oligomer to a toxic drug can convert it to a self-deliverable and safe nanotherapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Melanoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Pró-Fármacos/farmacologia , Taxoides/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Nus , Nanopartículas/química , Pró-Fármacos/química , Taxoides/química , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biochem Biophys Res Commun ; 545: 164-170, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33571907

RESUMO

Mammalian Transducin-like enhancer of split (TLE) confer global repression of numerous target genes in conjunction with a myriad of DNA-binding repressors. These factors have a major role in the regulation of multiple signal transduction pathways. Evidence have been obtained regarding the possible role of some of these proteins in cancer. TLE3 was suggested as a marker for increased chemosensitivity from pathological studies. Here we demonstrate, using the TCGA data base, differences in expression of this gene compared to TLE1 in several cancers. In-vitro transduction of a retrovirus encoding TLE3 to A549 lung cancer cells increased paclitaxel effectivity while TLE1 introduction to these cells decreased it. While TLE1 and TLE3 share ∼80% amino acid identity, we show that mutating or reconstituting an amino-terminal phosphorylation site, which is present only in TLE1 but absent from TLE3, and is evolutionary conserved, converts the activity of TLE1 to that of TLE3 like and vice versa. We repeated these results in an adipocytes differentiation system. Our results reveal how a single phosphorylation site can confer distinct qualitative or quantitative activities on highly homologous transcriptional regulators.


Assuntos
Proteínas Correpressoras/química , Proteínas Correpressoras/metabolismo , Células A549 , Adipócitos/citologia , Adipócitos/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sítios de Ligação/genética , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Linhagem Celular , Proteínas Correpressoras/genética , Sequência Conservada , Regulação da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Mutagênese Sítio-Dirigida , Fosforilação , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Taxoides/farmacologia
18.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619102

RESUMO

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/ß-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/ß-tubulin-GB1 complex.


Assuntos
Antineoplásicos/síntese química , Proteínas de Bactérias/síntese química , Produtos Biológicos/síntese química , Depsipeptídeos/síntese química , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/isolamento & purificação , Proteínas de Bactérias/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Colchicina/química , Colchicina/farmacologia , Cristalografia por Raios X , Cianobactérias/química , Depsipeptídeos/isolamento & purificação , Depsipeptídeos/farmacologia , Descoberta de Drogas , Células HCT116 , Humanos , Maitansina/química , Maitansina/farmacologia , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Pironas/química , Pironas/farmacologia , Taxoides/química , Taxoides/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/isolamento & purificação , Moduladores de Tubulina/farmacologia , Alcaloides de Vinca/química , Alcaloides de Vinca/farmacologia
19.
Sci Rep ; 11(1): 562, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436648

RESUMO

Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had been supported by many evidences Epigenetic regulation by miRNAs has been reported to influence cancer development and response to therapeutics, however, their role in OC resistance to paclitaxel (PTX) is unclear. Here, we conducted miRNA profiling in the responsive and PTX-resistant OC cell lines before and after treatment with epigenetic modulators. We reveal 157 miRNAs to be downregulated in the PTX-resistant cells compared to parental controls. The expression of five miRNAs (miRNA-7-5p, -204-3p, -501-5p, -3652 and -4286) was restored after epigenetic modulation, which was further confirmed by qPCR. In silico analysis of the signaling pathways targeted by the selected miRNAs identified the PI3K-AKT pathway as the primary target. Subsequent cDNA array analysis confirmed multiple PI3K-AKT pathway members such as AKT2, PIK3R3, CDKN1A, CCND2 and FGF2 to be upregulated in PTX-resistant cells. STRING analysis showed the deregulated genes in PTX-resistant cells to be primarily involved in cell cycle progression and survival. Thus, high throughput miRNA and cDNA profiling coupled with pathway analysis and data mining provide evidence for epigenetically regulated miRNAs-induced modulation of signaling pathways in PTX resistant OC cells. It paves the way to more in-depth mechanistic studies and new therapeutic strategies to combat chemoresistance.


Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Taxoides/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
Colloids Surf B Biointerfaces ; 199: 111535, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33360926

RESUMO

Cabazitaxel (CBZ) is a taxane derivative and an anti-microtubule agent effective against numerous cancers including drug-resistant cancers. In this study, CBZ loaded nanostructured lipid carriers (NLCs) were prepared by using Design-Expert (DoE) and optimized for various formulation parameters (ratio of lipids and surfactant concentration, homogenization speed and time). The optimized CBZ loaded NLCs formulation was characterized and evaluated through multiple physicochemical characterization techniques like FTIR, DSC, PXRD, SEM and in-vitro drug release. FTIR and DSC results suggested that NLCs entrapped drug inside and had no chemical bonding between drug and NLCs. SEM analysis confirmed homogeneous, spherical, and uniformly distributed NLCs. In-vitro cell culture studies suggested that CBZ loaded NLCs produced ∼ 6- and 2.5-times higher cytotoxicity against MDA-MB-468 and MCF-7 cell lines, respectively compared to pure drug. Cellular uptake of NLC was ∼2.5 and 2.1-fold higher than CBZ alone in MDA-MB-468 and MCF-7 cell lines, respectively. Furthermore, CBZ loaded NLCs produced significantly higher apoptosis and inhibited the mobility of MDA-MB-468 and MCF-7 cells. The results from this study demonstrate the utility of CBZ loaded NLCs as an effective treatment against breast cancer and NLCs as effective drug carriers to deliver the highly lipophilic drug such as CBZ.


Assuntos
Neoplasias da Mama , Nanoestruturas , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Humanos , Lipídeos , Células MCF-7 , Tamanho da Partícula , Taxoides/farmacologia , Taxoides/uso terapêutico
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