Zein Microneedles for Localized Delivery of Chemotherapeutic Agents to Treat Breast Cancer: Drug Loading, Release Behavior, and Skin Permeation Studies

Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

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A triple-drug nanotherapy to target breast cancer cells, cancer stem cells, and tumor vasculature

Cell Death and Disease ◽

10.1038/s41419-020-03308-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sara El-Sahli ◽

Khang Hua ◽

Andrew Sulaiman ◽

Jason Chambers ◽

Li Li ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Ex Vivo ◽

Chemotherapeutic Agents ◽

Hybrid Nanoparticles ◽

Cancer Drug ◽

Vascular Disrupting Agent

AbstractTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.

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Breast Cancer Drug Repurposing a Tool for a Challenging Disease

10.5772/intechopen.101378 ◽

2022 ◽

Author(s):

Jonaid Ahmad Malik ◽

Rafia Jan ◽

Sakeel Ahmed ◽

Sirajudheen Anwar

Keyword(s):

Breast Cancer ◽

Drug Discovery ◽

Molecular Targets ◽

Drug Repurposing ◽

Current Therapy ◽

Cancer Drug ◽

Drug Development Process ◽

Current Therapies ◽

Treat Breast Cancer ◽

Ovarian Syndrome

Drug repurposing is one of the best strategy for drug discovery. There are several examples where drug repurposing has revolutionized the drug development process, such as metformin developed for diabetes and is now employed in polycystic ovarian syndrome. Drug repurposing against breast cancer is currently a hot topic to look upon. With the continued rise in breast cancer cases, there is a dire need for new therapies that can tackle it in a better way. There is a rise of resistance to current therapies, so drug repurposing might produce some lead candidates that may be promising to treat breast cancer. We will highlight the breast cancer molecular targets, currently available drugs, problems with current therapy, and some examples that might be promising to treat it.

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Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Biomolecules ◽

10.3390/biom9120846 ◽

2019 ◽

Vol 9 (12) ◽

pp. 846 ◽

Cited By ~ 15

Author(s):

Samson Samuel ◽

Elizabeth Varghese ◽

Peter Kubatka ◽

Chris Triggle ◽

Dietrich Büsselberg

Keyword(s):

Breast Cancer ◽

Clinical Studies ◽

Current Knowledge ◽

Chemotherapeutic Agents ◽

Cancer Drug ◽

Rapid Progression ◽

Future Prospects ◽

Anti Cancer ◽

Cancer Agent ◽

Tumor Agent

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

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Epigallocatechin-3-Gallate Potentiates the Effect of Curcumin in Inducing Growth Inhibition and Apoptosis of Resistant Breast Cancer Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x14500803 ◽

2014 ◽

Vol 42 (05) ◽

pp. 1279-1300 ◽

Cited By ~ 34

Author(s):

Shengpeng Wang ◽

Ruie Chen ◽

Zhangfeng Zhong ◽

Zhi Shi ◽

Meiwan Chen ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Growth Inhibition ◽

Chemotherapeutic Agents ◽

Cancer Drug ◽

Cancer Resistance ◽

Breast Cancer Chemotherapy ◽

Cancer Drug Resistance ◽

Context Specific ◽

Mcf 7

Drug resistance remains an on-going challenge in breast cancer chemotherapy. Combination of two or more drugs is an effective strategy to access context-specific multiple targets and overcome undesirable toxicity that is almost inevitable in single-drug chemotherapy. Many plant food-derived polyphenolic compounds have been proven to modulate many key factors responsible for cancer drug resistance, which makes them a promising group of low toxicity candidates for reversing cancer resistance. In this study, we analyzed the combination effect of two chemopreventive polyphenols, curcumin (Cur) and epigallocatechin-3-gallate (EGCG), in combating resistant breast cancer. Our present results showed that EGCG significantly enhanced the growth inhibition and apoptosis in both doxorubicin (DOX)-sensitive and resistant MCF-7 cells induced by Cur. The mechanism may be related to the further activation of caspase-dependent apoptotic signaling pathways and the enhanced cellular incorporation of Cur by inhibiting P-glycoprotein (P-gp) pump function. Moreover, Cur and EGCG in combination could enhance the toxicity of DOX and increase the intracellular level of DOX in resistant MCF-7 cells. Our findings with this practical combination of Cur and EGCG encourage us to move on to a promising strategy for successful treatment of human breast cancer resistance by combining two low-toxic chemotherapeutic agents from diet.

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Anticancer Effect of Alginate-Chitosan Hydrogel Loaded with Curcumin and Chrysin on Lung and Breast Cancer Cell Lines

Current Drug Delivery ◽

10.2174/1567201818666210813142007 ◽

2021 ◽

Vol 18 ◽

Author(s):

Farhad Abbasalizadeh ◽

Effat Alizadeh ◽

Seyyed Mohammad Bagher Fazljou ◽

Mohammadali Torbati ◽

Abolfazl Akbarzadeh

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Lines ◽

Drug Loading ◽

Chemotherapeutic Agents ◽

Breast Cancer Cell Lines ◽

Gelation Mechanism ◽

Dapi Staining ◽

Chitosan Hydrogel ◽

Chitosan Hydrogels

Objective: We conducted the present study to investigate the anticancer effects of curcumin and chrysin loaded in the alginate-chitosan hydrogel on breast cancer (T47D) and lung cancer (A549). Background: Cancer, which is defined as abnormal cell growth, is one of the biggest public health problems in the world. Natural compounds, such as polyphenols, are used as chemo-preventive and chemotherapeutic agents in different types of cancer owing to their antioxidant, antineoplastic, and cytotoxic properties. To improve their bioavailability and releasing behavior, hydrogel systems with high drug loading and stability and hydrophilic nature have been designed. Methods: The curcumin-chrysin-loaded alginate-chitosan hydrogels were prepared through the ionic gelation mechanism utilizing CaCl2. The prepared hydrogels were studied by using the Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The MTT and DAPI staining assays were employed for cytotoxicity and apoptosis studies of curcumin-chrysin-loaded alginate-chitosan hydrogels. The effects of the curcumin-chrysin-loaded alginate-chitosan hydrogels on the cell cycle of cell lines T47D and A549 were also evaluated using the propidium iodide staining. Results: The FTIR indicated specific bands at 1607 and 1422 cm-1 (the carbonyl of alginate) at 834 cm-1 (sodium alginate), 1447 cm-1, and 1026 cm-1 (COOH and C-O stretching bands alginate and chitosan). The curcumin-chrysin-loaded alginate-chitosan hydrogels could significantly (p<0.05) reduce the viability and induce apoptosis, Morover, cause G2/M arrest of the cell cycle in both A549 and T47D cell lines. Conclusion: The alginate-chitosan hydrogels could work best as an enhanced anticancer drug delivery system.

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