Elsevier

Drug Discovery Today

Volume 25, Issue 9, September 2020, Pages 1651-1667
Drug Discovery Today

Review
Keynote
Cancer stem cells and nanomedicine: new opportunities to combat multidrug resistance?

https://doi.org/10.1016/j.drudis.2020.07.023Get rights and content

Highlights

  • Combined efflux transport and enzyme activity induces cancer multidrug resistance.

  • A subpopulation of stem-like cells (CSCs) induces the renewal of cancer.

  • Conventional chemotherapy can destroy cancer high proliferating cells but not CSCs.

  • Natural compounds or their derivatives can be efficacious against CSCs.

  • Nanotechnologies can support combinational treatments for cancer eradication.

‘Multidrug resistance’ (MDR) is a difficult challenge for cancer treatment. The combined role of cytochrome P450 enzymes (CYPs) and active efflux transporters (AETs) in cancer cells appears relevant in inducing MDR. Chemotherapeutic drugs can be substrates of both CYPs and AETs and CYP inducers or inhibitors can produce the same effects on AETs. In addition, a small subpopulation of cancer stem-like cells (CSCs) appears to survive conventional chemotherapy, leading to recurrent disease. Natural products appear efficacious against CSCs; their combinational treatments with standard chemotherapy are promising for cancer eradication, in particular when supported by nanotechnologies.

Introduction

Cancer is one of the main causes of death worldwide [1]. Remarkable progress in the treatment of cancer over the past five decades has been counteracted by the onset of cancer resistance against most therapies [2]. In general, the drug resistance of cancers can be sorted into two categories: intrinsic or acquired. Intrinsic resistance to chemotherapy occurs in patients retaining resistant phenotypes before the start of treatments, whereas acquired resistance can arise during or after treatment of patients who are initially responsive. Often, the acquired resistance against a specific drug can also extend to other drugs [3]. In particular, chemotherapeutic drugs inhibit fast-replicative cells, including cancer cells [4]. Even though chemotherapy constitutes a valid choice for cancer therapy, it is possible that, after repeated treatments, cancer cells not only become resistant to the specific chemotherapeutic agent used, but also cross-resistant to other cytotoxic drugs with different chemical structures or mechanisms of action [5]. This phenomenon, called MDR, is one of the most difficult challenges for cancer treatment [6].

Cancer cells can develop MDR through several mechanisms, including (i) activation of detoxifying systems; (ii) increased drug efflux; (iii) decreased drug uptake; (iv) activation of DNA repair mechanisms; and (v) evasion of drug-induced apoptosis. The increase in drug efflux is the most important mechanism related to drug resistance [7]; moreover, drug efflux increase is often combined with the upregulation of enzymes involved in the metabolism of anticancer agents [8]. Therefore, enzymes and efflux transporters expressed by cancer cells appear to be crucial not only for their proliferation, but also for their resistance to clinical treatments. Furthermore, research also suggests that CSCs, a subgroup of cancer cells characterized by stem-like properties, significantly contribute to chemoresistance and cancer relapse, being able to self-renew and differentiate into heterogeneous cancer cell lineages in response to chemotherapeutic agents [9].

In this review, we describe several CYP enzymes and efflux transporters related to cancer, given that MDR can arise from their combined upregulation. In addition, we describe current strategies proposed to tackle MDR, taking into account the contribution of CSCs and the importance of the nanotechnologies in the design and development of new therapeutic systems.

Section snippets

CYP enzymes in cancer cells

CYP is a superfamily of enzymes that contribute to the metabolism of exogenous and endogenous compounds in our body, particularly during Phase I [10]. The liver and small intestine show the highest concentrations of CYP enzymes [11], although they are also expressed in other healthy tissues [1]. However, some are overexpressed in tumor tissues. For example, the CYP1 family includes CYP1A1, CYP1A2, and CYP1B1 [12], among which CYP1B1 appears abundantly expressed in the prostate, breast, and

Inhibition of CYP: potential new anticancer therapies

The inhibition of specific CYP enzymes is a new and promising therapeutic strategy against cancer. CYP2J2, expressed in the heart for the metabolism of polyunsaturated fatty acids to cardioactive metabolites [14], is one focus for research because it is upregulated in multiple cancers [15].

The high expression of CYP2J2 in human carcinomas appears as a general phenomenon rather than type specific; thus, its inhibition can hold significant promise for the treatment of neoplastic diseases.

Relation of the chemotherapeutic action of plant-derived compounds to mammalian P450 enzymes

Several chemotherapeutic agents, such as vinca alkaloids, taxanes, and camptothecins, are phytotoxins synthesized by plant P450 cytochromes [27]. These compounds evolved as defensive mechanisms of plants against animal predation 27, 45, 46. By contrast, the first stages of the evolution of mammalian P450 s enabled animals to defend themselves against phytotoxins 27, 31, 32. Therefore, P450 s were at the forefront of plant–animal coevolution at the chemical level [27].

The enhanced expression of

CSCs can be recognized and characterized based on specific properties

CSCs, similar to normal stem cells, are able to renew by maintaining an undifferentiated state. However, this process is dysregulated, leading to CSC overpopulation, which drives tumor growth. In particular, an increase in symmetric cell division (which produces two stem cell daughters) with respect to asymmetric division (which produces one stem and no-stem daughter cells) separates CSCs from normal stem cells [47]. Therefore, cancer cells in solid tumors appear distributed according to a

What therapeutic approaches do the models above described suggest?

It is unclear whether the models described earlier are fully representative of reality. Nevertheless, the therapeutic approaches that can be proposed against cancer are dependent on these models in terms of their potential efficacy.

According to the stochastic model, chemotherapy is designed to kill rapidly proliferating cells showing high efficacy. However, this efficacy can be strongly reduced by the onset of MDR. This could be counteracted by using efflux transporter inhibitors, even though

How can we target CSCs?

Drugs able to destroy CSCs without damaging healthy cells are available and most are naturally derived compounds 52, 61, 105, 127, suggesting that their ability to kill CSCs is related to previous evolutionary stages of the chemical arms race between animal and plant cells 27, 52. The mechanisms of action of these compounds differ from those of conventional chemotherapy, which is designed to kill rapidly proliferating cells. Unfortunately, CSCs are difficult to target, being normally protected

Concluding remarks

Cancer MDR is a phenomenon related both to rapidly proliferating cells, constituting the bulk of tumors, and to CSCs, localized in tumoral niches that are difficult to target. Combined therapies supported by nanotechnologies can weaken the tumoral bulk, killing CSCs, and, thus, appear promising for cancer eradication. Prodrugs obtained by the conjugation of conventional therapeutic drugs with novel anti-CSC agents could constitute tools to obtain new self-assembled or innovative nanocarriers

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

Support from the University of Ferrara, Italy (2018-FAR.L-DA_002) in the frame of the project FAR2018 is gratefully acknowledged.

Glossary

Androgen deprivation therapy (ADT)
a type of treatment for PC that blocks the effects of androgens and can slow PC growth.
Cancer stem cells (CSC)
subpopulations of cancer cells sharing similar characteristics as normal stem or progenitor cells, such as self-renewal ability and multi-lineage differentiation, to drive tumor growth and heterogeneity. Throughout cancer progression, CSCs can further be induced from differentiated cancer cells via adaptation and crosstalk with the TME as well as in

Alessandro Dalpiaz is associate professor of biopharmaceutics in the Department of Chemical and Pharmaceutical Sciences of the Ferrara University, Italy. He was previously a research fellow at the Leiden/Amsterdam Centre for Drug Research of Leiden University, The Netherlands. He is an author of more than 100 peer-reviewed manuscripts. His research topics include in vitro models and in vivo studies of drug transport, drug stability studies in physiological fluids and prodrugs or micro- and

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    Alessandro Dalpiaz is associate professor of biopharmaceutics in the Department of Chemical and Pharmaceutical Sciences of the Ferrara University, Italy. He was previously a research fellow at the Leiden/Amsterdam Centre for Drug Research of Leiden University, The Netherlands. He is an author of more than 100 peer-reviewed manuscripts. His research topics include in vitro models and in vivo studies of drug transport, drug stability studies in physiological fluids and prodrugs or micro- and nanodelivery systems improving the therapeutic pattern of drugs.

    Guglielmo Paganetto is a lecturer in the biotechnology of medical plants at the University of Ferrara. He was awarded a BSc in chemistry in 1979. In 1981, he joined the Giulio Natta Research Center, where he became a manager of the toxicological laboratory, where he studied bioabsorbable polymers as drug delivery systems, mutagenesis, and carcinogenesis. He is an author of 60 peer-reviewed papers and two monographs. His current research includes the chemopreventive and pharmacological actions of phytochemicals.

    Giada Botti is a first-year PhD student in chemical sciences, University of Ferrara. She was awarded a BSc in medicinal chemistry in 2018. Her research currently focuses on pharmacokinetic and permeation studies of biologically active natural compounds and synthetic derivatives using in vitro cellular models, and the production of new biocompatible nanosystems able to target drugs to their active sites.

    Barbara Pavan is assistant professor in the Department of Biomedical Sciences and Specialist Surgery at the University of Ferrara, Italy. She holds a PhD in Cell and Molecular Biology and she was a research fellow at the Leiden/Amsterdam Center for Drug Research of Leiden University. She has authored 83 peer-reviewed papers. Her research integrates cell physiology with drug delivery, development of biohybrid neural devices, and microfluidic platforms of human brain neurons.

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