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Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer.

ABSTRACT: Targeted delivery of drugs to tumor cells, which circumvent resistance mechanisms and induce cell killing, is a lingering challenge that requires innovative solutions. Here, we provide two bioengineered strategies in which nanotechnology is blended with cancer medicine to preferentially target distinct mechanisms of drug resistance. In the first 'case study', we demonstrate the use of lipid-drug conjugates that target molecular signaling pathways, which result from taxane-induced drug tolerance via cell surface lipid raft accumulations. Through a small molecule drug screen, we identify a kinase inhibitor that optimally destroys drug tolerant cancer cells and conjugate it to a rationally-chosen lipid scaffold, which enhances anticancer efficacy in vitro and in vivo. In the second 'case study', we address resistance mechanisms that can occur through exocytosis of nanomedicines. Using adenocarcinoma HeLa and MCF-7 cells, we describe the use of gold nanorod and nanoporous vehicles integrated with an optical antenna for on-demand, photoactivation at ~650 nm enabling release of payloads into cells including cytotoxic anthracyclines. Together, these provide two approaches, which exploit engineering strategies capable of circumventing distinct resistance barriers and induce killing by multimodal, including nanophotonic mechanisms.

SUBMITTER: Saha T

PROVIDER: S-EPMC8478290 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer.

Saha Tanmoy T Mondal Jayanta J Khiste Sachin S Lusic Hrvoje H Hu Zhang-Wei ZW Jayabalan Ruparoshni R Hodgetts Kevin J KJ Jang HaeLin H Sengupta Shiladitya S Eunice Lee Somin S Park Younggeun Y Lee Luke P LP Goldman Aaron A

Nanophotonics (Berlin, Germany) 20210625 12

Targeted delivery of drugs to tumor cells, which circumvent resistance mechanisms and induce cell killing, is a lingering challenge that requires innovative solutions. Here, we provide two bioengineered strategies in which nanotechnology is blended with cancer medicine to preferentially target distinct mechanisms of drug resistance. In the first 'case study', we demonstrate the use of lipid-drug conjugates that target molecular signaling pathways, which result from taxane-induced drug tolerance ...[more]

PMID: 34589378

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Project description:Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.

Project description:The levels of different molecules in the cell are rhythmically cycled by the molecular clock present at the cellular level. The circadian rhythm is closely linked to the metabolic processes in the cells by an underlying mechanism whose intricacies need to be thoroughly investigated. Nevertheless, Nrf2 has been identified as an essential bridge between the circadian clock and cellular metabolism and is activated by the by-product of cellular metabolism like hydrogen peroxide. Once activated it binds to the specific DNA segments and increases the transcription of several genes that play a crucial role in the normal functioning of the cell. The central clock located in the suprachiasmatic nucleus of the anterior hypothalamus synchronizes the timekeeping in the peripheral tissues by integrating the light-dark input from the environment. Several studies have demonstrated the role of circadian rhythm as an effective tumor suppressor. Tumor development is triggered by the stimulation or disruption of signaling pathways at the cellular level as a result of the interaction between cells and environmental stimuli. Oxidative stress is one such external stimulus that disturbs the prooxidant/antioxidant equilibrium due to the loss of control over signaling pathways which destroy the bio-molecules. Altered Nrf2 expression and impaired redox balance are associated with various cancers suggesting that Nrf2 targeting may be used as a novel therapeutic approach for treating cancers. On the other hand, Nrf2 has also been shown to enhance the resistance of cancer cells to chemotherapeutic agents. We believe that maximum efficacy with minimum side effects for any particular therapy can be achieved if the treatment strategy regulates the circadian rhythm. In this review, we discuss the various molecular mechanisms interlinking the circadian rhythm with the Nrf2 pathway and contributing to breast cancer pathogenesis, we also talk about how these two pathways work in close association with the cell cycle which is another oscillatory system, and whether this interplay can be exploited to overcome drug resistance during chemotherapy.

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Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer.

Publications

Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer.

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