Review

Jump to: Other

26 pages, 3889 KiB

Open AccessReview

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance

by Michelle K. Greene, Michael C. Johnston and Christopher J. Scott

Cancers 2021, 13(24), 6175; https://doi.org/10.3390/cancers13246175 - 07 Dec 2021

Cited by 21 | Viewed by 3978

The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its [...] Read more.

The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

23 pages, 1088 KiB

Open AccessReview

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

by Christopher McCann and Emma M. Kerr

Cancers 2021, 13(13), 3351; https://doi.org/10.3390/cancers13133351 - 03 Jul 2021

Cited by 11 | Viewed by 3413

Abstract

Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries [...] Read more.

Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

25 pages, 1644 KiB

Open AccessReview

Dying to Survive—The p53 Paradox

by Andrea Lees, Tamas Sessler and Simon McDade

Cancers 2021, 13(13), 3257; https://doi.org/10.3390/cancers13133257 - 29 Jun 2021

Cited by 15 | Viewed by 4296

Abstract

The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount [...] Read more.

The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

17 pages, 1538 KiB

Open AccessReview

Life after Cell Death—Survival and Survivorship Following Chemotherapy

by Tamara Mc Erlain, Aileen Burke and Cristina M. Branco

Cancers 2021, 13(12), 2942; https://doi.org/10.3390/cancers13122942 - 11 Jun 2021

Cited by 2 | Viewed by 3220

Abstract

To prevent cancer cells replacing and outnumbering their functional somatic counterparts, the most effective solution is their removal. Classical treatments rely on surgical excision, chemical or physical damage to the cancer cells by conventional interventions such as chemo- and radiotherapy, to eliminate or [...] Read more.

To prevent cancer cells replacing and outnumbering their functional somatic counterparts, the most effective solution is their removal. Classical treatments rely on surgical excision, chemical or physical damage to the cancer cells by conventional interventions such as chemo- and radiotherapy, to eliminate or reduce tumour burden. Cancer treatment has in the last two decades seen the advent of increasingly sophisticated therapeutic regimens aimed at selectively targeting cancer cells whilst sparing the remaining cells from severe loss of viability or function. These include small molecule inhibitors, monoclonal antibodies and a myriad of compounds that affect metabolism, angiogenesis or immunotherapy. Our increased knowledge of specific cancer types, stratified diagnoses, genetic and molecular profiling, and more refined treatment practices have improved overall survival in a significant number of patients. Increased survival, however, has also increased the incidence of associated challenges of chemotherapy-induced morbidity, with some pathologies developing several years after termination of treatment. Long-term care of cancer survivors must therefore become a focus in itself, such that along with prolonging life expectancy, treatments allow for improved quality of life. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Graphical abstract

26 pages, 4252 KiB

Open AccessReview

Therapeutics Targeting the Core Apoptotic Machinery

by Claudia Hamilton, Jennifer P. Fox, Daniel B. Longley and Catherine A. Higgins

Cancers 2021, 13(11), 2618; https://doi.org/10.3390/cancers13112618 - 26 May 2021

Cited by 13 | Viewed by 3729 | Correction

Abstract

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct [...] Read more.

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

22 pages, 2006 KiB

Open AccessReview

Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

by Ziad Omran, Mahmood H. Dalhat, Omeima Abdullah, Mohammed Kaleem, Salman Hosawi, Fahd A Al-Abbasi, Wei Wu, Hani Choudhry and Mahmoud Alhosin

Cancers 2021, 13(8), 1916; https://doi.org/10.3390/cancers13081916 - 15 Apr 2021

Cited by 6 | Viewed by 2825

Abstract

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as [...] Read more.

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

14 pages, 2542 KiB

Open AccessReview

Resistance to Cell Death in Mucinous Colorectal Cancer—A Review

by Emer O’Connell, Ian S. Reynolds, Deborah A. McNamara, John P. Burke and Jochen H. M. Prehn

Cancers 2021, 13(6), 1389; https://doi.org/10.3390/cancers13061389 - 19 Mar 2021

Cited by 14 | Viewed by 4078

Abstract

Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic [...] Read more.

Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-X_L, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

22 pages, 3716 KiB

Open AccessEditor’s ChoiceReview

A 3D View of Colorectal Cancer Models in Predicting Therapeutic Responses and Resistance

by Eileen Reidy, Niamh A. Leonard, Oliver Treacy and Aideen E. Ryan

Cancers 2021, 13(2), 227; https://doi.org/10.3390/cancers13020227 - 10 Jan 2021

Cited by 42 | Viewed by 5616

Abstract

Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect [...] Read more.

Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients with late stage CRC display resistance to multiple different therapeutics. An important aspect in developing effective therapeutics for CRC patients is understanding the interactions that take place in the tumor microenvironment (TME), as it has been shown to contribute to drug resistance in vivo. Much research over the past 100 years has focused on 2D monolayer cultures or in vivo studies, however, the efficacy in translating these to the clinic is very low. More recent studies are turning towards developing an effective 3D model of CRC that is clinically relevant, that can recapitulate the TME in vitro and bridge the gap between 2D cultures and in vivo studies, with the aim of reducing the use of animal models in the future. This review summarises the advantages and limitations of different 3D CRC models. It emphasizes how different 3D models may be optimised to study cellular and extracellular interactions that take place in the TME of CRC in an effort to allow the development of more translatable effective treatment options for patients. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

12 pages, 3828 KiB

Open AccessReview

BNIP3 in Lung Cancer: To Kill or Rescue?

by Anna S. Gorbunova, Maria A. Yapryntseva, Tatiana V. Denisenko and Boris Zhivotovsky

Cancers 2020, 12(11), 3390; https://doi.org/10.3390/cancers12113390 - 16 Nov 2020

Cited by 23 | Viewed by 3380

Abstract

Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in [...] Read more.

Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in autophagy, metabolic pathways, and metastasis-related processes in different tumor types. Lung cancer is one of the most aggressive types of cancer, which is often diagnosed at an advanced stage. Therefore, there is still urgent demand for reliable biochemical markers for lung cancer and its efficient treatment. Mitochondria functioning and mitochondrial proteins, including BNIP3, have a strong impact on lung cancer development and progression. Here, we summarized current knowledge about the BNIP3 gene and protein features and their role in cancer progression, especially in lung cancer in order to develop new therapeutic approaches associated with BNIP3. Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

► Show Figures

Figure 1

Other

Jump to: Review

1 pages, 158 KiB

Open AccessCorrection

Correction: Hamilton et al. Therapeutics Targeting the Core Apoptotic Machinery. Cancers 2021, 13, 2618

by Claudia Hamilton, Jennifer P. Fox, Daniel B. Longley and Catherine A. Higgins

Cancers 2022, 14(6), 1441; https://doi.org/10.3390/cancers14061441 - 11 Mar 2022

Viewed by 1255

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)

Journal Menu

Journal Browser

Drug Resistance and Cell Death in Cancer

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI