Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 12334

Special Issue Editor

School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK
Interests: drug discovery; pro-drugs; drug conjugates; anti-cancer drugs; antimicrobial peptides; organic synthesis; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce the new Special Issue for Pharmaceutics entitled "Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy".

Early diagnosis and treatment of cancer are the most likely measures to lead to a cure. However, many cancers are diagnosed at an advanced stage, or are at risk of recurrence, often accompanied by drug resistance. Improving patient survival and quality of life in advanced disease presents a major challenge in oncology. There have been some market successes in recent years, for example, in the areas of immunotherapy and selective kinase inhibitors, but there is still significant unmet clinical need. Therefore, therapies to manage locally advanced and metastatic cancer by targeting the mechanisms involved in drug resistance and metastasis continue to be an important field of research. 

This Special Issue aims to highlight the latest drug design research in developing therapeutic strategies to target the pathways involved in drug resistance and metastatic processes in cancer.

Dr. Sharon Rossiter
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • oncology
  • metastasis
  • cancer targets
  • drug resistance
  • drug discovery
  • drug targeting
  • drug delivery

Published Papers (5 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

18 pages, 3807 KiB  
Article
The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells
by Michel Demeule, Cyndia Charfi, Jean-Christophe Currie, Alain Zgheib, Bogdan Alexandru Danalache, Richard Béliveau, Christian Marsolais and Borhane Annabi
Pharmaceutics 2022, 14(9), 1910; https://doi.org/10.3390/pharmaceutics14091910 - 09 Sep 2022
Cited by 7 | Viewed by 2683
Abstract
Background: Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemoresistance phenotype of human triple-negative breast CSC [...] Read more.
Background: Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemoresistance phenotype of human triple-negative breast CSC (hTNBCSC) and ovarian CSC (hOvCSC) is unknown. Methods and Results: Immunophenotyping of hTNBCSC and hOvCSC was performed by flow cytometry and confirmed the expression of SORT1, and of CSC markers CD133, NANOG, and SOX2. Western blotting demonstrated the expression of the drug efflux pumps from the P-gp family members, ABCB1 and ABCB5. The cellular uptake of the fluorescent Alexa488-peptide from TH1902 was inhibited upon siRNA-mediated repression of SORT1 or upon competition with SORT1 ligands. In contrast to docetaxel, TH1902 inhibited in vitro migration, induced cell apoptosis and lead to G2/M cell cycle arrest of the hTNBCSC. These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. In vivo, using immunosuppressed nude mice xenografts, TH1902 significantly inhibited the growth of hTNBCSC and hOvCSC xenografts (~80% vs. ~35% for docetaxel) when administered weekly as intravenous bolus for three cycles at 15 mg/kg, a dose equivalent to the maximal tolerated dose of docetaxel. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. Conclusions: Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
Show Figures

Figure 1

14 pages, 2438 KiB  
Article
SRC Kinase-Mediated Tyrosine Phosphorylation of TUBB3 Regulates Its Stability and Mitotic Spindle Dynamics in Prostate Cancer Cells
by Alan Alfano, Jin Xu, Xi Yang, Dhanraj Deshmukh and Yun Qiu
Pharmaceutics 2022, 14(5), 932; https://doi.org/10.3390/pharmaceutics14050932 - 25 Apr 2022
Cited by 7 | Viewed by 1791
Abstract
Tubulin is an integral part of the cytoskeleton and plays a pivotal role in cellular signaling, maintenance, and division. β-tubulin is also the molecular target for taxane compounds such as docetaxel (DTX) and cabazitaxel (CTX), both first-line treatments for several solid cancers. Increased [...] Read more.
Tubulin is an integral part of the cytoskeleton and plays a pivotal role in cellular signaling, maintenance, and division. β-tubulin is also the molecular target for taxane compounds such as docetaxel (DTX) and cabazitaxel (CTX), both first-line treatments for several solid cancers. Increased expression of Class III β-tubulin (TUBB3), a primarily neural isoform of β-tubulin, correlates with taxane resistance and poor prognosis. Although tyrosine kinase c-Src has been implicated to phosphorylate β-tubulins during both hematopoietic and neural differentiation, the mechanisms by which Src modulates tubulins functions are still poorly understood. Here, we report, for the first time, that TUBB3 is phosphorylated at Tyrosine 340 (Y340) by c-SRC in prostate cancer cells. We also showed that Y340 phosphorylation regulates TUBB3 protein stability and subcellular localization. Furthermore, we demonstrated that inhibition of SRC kinase activity compromises spindle stability in mitotic cells, at least partly due to the lack of TUBB3 Y340 phosphorylation. Given the importance of TUBB3 as a clinical biomarker of poor prognosis and drug resistance, characterization of TUBB3 posttranslational regulation could potentially serve as new biomarkers for disease recurrence and/or treatment failure. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
Show Figures

Figure 1

16 pages, 3082 KiB  
Article
Regulation of p27 (Kip1) by Ubiquitin E3 Ligase RNF6
by Dhanraj Deshmukh, Jin Xu, Xi Yang, Hermela Shimelis, Shengyun Fang and Yun Qiu
Pharmaceutics 2022, 14(4), 802; https://doi.org/10.3390/pharmaceutics14040802 - 06 Apr 2022
Cited by 1 | Viewed by 1746
Abstract
The cyclin-dependent kinase inhibitor p27 (Kip1) is an important regulator of the G1/S checkpoint. It is degraded by the SCF-SKP2 complex in late G1 thereby allowing cells to progress to the S phase. Here we investigated the role of the E3 ubiquitin ligase [...] Read more.
The cyclin-dependent kinase inhibitor p27 (Kip1) is an important regulator of the G1/S checkpoint. It is degraded by the SCF-SKP2 complex in late G1 thereby allowing cells to progress to the S phase. Here we investigated the role of the E3 ubiquitin ligase RNF6 (Ring Finger Protein 6) in cell cycle progression in prostate cancer cells. Our data demonstrate that RNF6 can promote cell cycle progression by reducing the levels of p27. Knockdown of RNF6 led to an increase in the stability of p27 and to the arrest of cells in the G1 phase. RNF6 interacted with p27 via its KIL domain and this interaction was found to be phosphorylation independent. RNF6 enhanced ubiquitination and subsequent degradation of p27 in the early G0/G1 phase of the cell cycle. Knockdown of RNF6 expression by short hairpin RNA led to inhibition of the CDK2/Cyclin E complex thereby reducing phosphorylation of Retinoblastoma protein (Rb) and to a subsequent decrease in cell cycle progression and proliferation. Our data suggest that RNF6 acts as a negative regulator for p27kip1 leading to its proteasome-dependent degradation in the early G0/G1 phase of the cell cycle. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
Show Figures

Figure 1

Review

Jump to: Research

13 pages, 1268 KiB  
Review
The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
by Andrew Wu, Kelly A. Turner, Adrian Woolfson and Xiaoyan Jiang
Pharmaceutics 2023, 15(3), 958; https://doi.org/10.3390/pharmaceutics15030958 - 16 Mar 2023
Cited by 1 | Viewed by 1830
Abstract
Despite the development of therapeutic agents that selectively target cancer cells, relapse driven by acquired drug resistance and resulting treatment failure remains a significant issue. The highly conserved Hedgehog (HH) signaling pathway performs multiple roles in both development and tissue homeostasis, and its [...] Read more.
Despite the development of therapeutic agents that selectively target cancer cells, relapse driven by acquired drug resistance and resulting treatment failure remains a significant issue. The highly conserved Hedgehog (HH) signaling pathway performs multiple roles in both development and tissue homeostasis, and its aberrant regulation is known to drive the pathogenesis of numerous human malignancies. However, the role of HH signaling in mediating disease progression and drug resistance remains unclear. This is especially true for myeloid malignancies. The HH pathway, and in particular the protein Smoothened (SMO), has been shown to be essential for regulating stem cell fate in chronic myeloid leukemia (CML). Evidence suggests that HH pathway activity is critical for maintaining the drug-resistant properties and survival of CML leukemic stem cells (LSCs), and that dual inhibition of BCR-ABL1 and SMO may comprise an effective therapeutic strategy for the eradication of these cells in patients. This review will explore the evolutionary origins of HH signaling, highlighting its roles in development and disease, which are mediated by canonical and non-canonical HH signaling. Development of small molecule inhibitors of HH signaling and clinical trials using these inhibitors as therapeutic agents in cancer and their potential resistance mechanisms, are also discussed, with a focus on CML. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
Show Figures

Figure 1

48 pages, 3370 KiB  
Review
Emerging Nanotherapeutic Approaches to Overcome Drug Resistance in Cancers with Update on Clinical Trials
by Syed Nasir Abbas Bukhari
Pharmaceutics 2022, 14(4), 866; https://doi.org/10.3390/pharmaceutics14040866 - 15 Apr 2022
Cited by 18 | Viewed by 3431
Abstract
A key issue with modern cancer treatments is the emergence of resistance to conventional chemotherapy and molecularly targeted medicines. Cancer nanotherapeutics were created in order to overcome the inherent limitations of traditional chemotherapeutics. Over the last few decades, cancer nanotherapeutics provided unparalleled opportunities [...] Read more.
A key issue with modern cancer treatments is the emergence of resistance to conventional chemotherapy and molecularly targeted medicines. Cancer nanotherapeutics were created in order to overcome the inherent limitations of traditional chemotherapeutics. Over the last few decades, cancer nanotherapeutics provided unparalleled opportunities to understand and overcome drug resistance through clinical assessment of rationally designed nanoparticulate delivery systems. In this context, various design strategies such as passive targeting, active targeting, nano-drug, and multimodal nano-drug combination therapy provided effective cancer treatment. Even though cancer nanotherapy has made great technological progress, tumor biology complexity and heterogeneity and a lack of comprehensive knowledge of nano-bio interactions remain important roadblocks to future clinical translation and commercialization. The current developments and advancements in cancer nanotherapeutics employing a wide variety of nanomaterial-based platforms to overcome cancer treatment resistance are discussed in this article. There is also a review of various nanotherapeutics-based approaches to cancer therapy, including targeting strategies for the tumor microenvironment and its components, advanced delivery systems for specific targeting of cancer stem cells (CSC), as well as exosomes for delivery strategies, and an update on clinical trials. Finally, challenges and the future perspective of the cancer nanotherapeutics to reverse cancer drug resistance are discussed. Full article
(This article belongs to the Special Issue Targeting Drug Resistance and Metastatic Pathways for Cancer Therapy)
Show Figures

Figure 1

Back to TopTop