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Current Research on Cancer Biology and Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 17095

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Special Issue Editor

Prof. Dr. Rafael Coveñas Rodríguez

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Guest Editor

Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neuroscience of Castilla and León (INCYL), University of Salamanca, c/ Pintor Fernando Gallego 1, 37007 Salamanca, Spain
Interests: cancer and anticancer peptides; substance P/neurokinin-1 receptor system; neurokinin-1 receptor antagonists
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Special Issue Information

Dear Colleagues,

Cancer caused 10 million deaths in 2020 and remains a major health problem worldwide. Surgery, chemotherapy, and radiotherapy are the current cancer treatments, but unfortunately, the results are in many cases unsatisfactory. The development of promising cancer research fields (new cytostatics, stem cells, human genome) has not been translated into better perspectives for many cancer patients. To improve the diagnosis and treatment of tumors, novel specific anticancer strategies showing enhanced antitumor effects and decreased toxicity must be explored.

Cancer cells evade the immune system and show resistance to anticancer therapies, leading to cancer cell proliferation, survival, invasion, and metastasis. These mechanisms, as well as angiogenesis, are regulated by different ligands, receptors, and intracellular cascades that regulate the genetic/protein machinery of cancer cells; thus, anticancer drugs must specifically block these cellular events. This has opened up new research lines to explore new therapeutic strategies focused on targetable molecules. Accordingly, the main aim of this Special Issue is to increase knowledge about potential targetable molecules involved in previous mechanisms such as peptides, signal transduction molecules, transcription factors, kinases, DNA damage repair enzymes, and epigenetic regulatory proteins. Thus, new antiproliferative, antimetastatic, and antiangiogenic strategies are welcome, as well as apoptotic inducers, signal transduction inhibitors, cytotoxic peptide-conjugate-based cancer therapy, gene expression modulators, hormone therapies, and peptide-receptor radionuclide therapy. Studies focused on the function–structure relationships between ligands and receptors for the design and synthesis of new and more effective anticancer compounds are also welcome.

I hope that this Special Issue opens the door to developing promising molecular targets, to blocking tumor development, and to developing new compounds capable of specifically destroying tumor cells. New anticancer strategies targeting tumor-specific molecular derangements must serve to improve the diagnosis and treatment of tumors and increase the cure rate and quality of life of cancer patients.

Prof. Dr. Rafael Coveñas Rodríguez
Guest Editor

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Keywords

antiangiogenic
anticancer therapy
antimetastatic
apoptosis
antiproliferative
cancer
peptides
signaling molecules
transcription factors
tumor

Published Papers (11 papers)

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Editorial

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4 pages, 179 KiB

Open AccessEditorial

Editorial for the Special Issue “Current Research on Cancer Biology and Therapeutics”

by Rafael Coveñas

Int. J. Mol. Sci. 2024, 25(5), 2802; https://doi.org/10.3390/ijms25052802 - 28 Feb 2024

Viewed by 384

Abstract

Cancer is a major health problem, in 2020 caused 10 million deaths and in 2040, 28,4 million patients suffering from the disease are expected [...] Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

Research

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10 pages, 1385 KiB

Open AccessCommunication

The Effect of Silencing Fatty Acid Elongase 4 and 6 Genes on the Proliferation and Migration of Colorectal Cancer Cells

by Aleksandra Czumaj, Jarosław Kobiela, Adriana Mika, Emmanouil Pappou and Tomasz Śledziński

Int. J. Mol. Sci. 2023, 24(24), 17615; https://doi.org/10.3390/ijms242417615 - 18 Dec 2023

Cited by 1 | Viewed by 763

Abstract

Colorectal cancer (CRC) cells show some alterations in lipid metabolism, including an increased fatty acid elongation. This study was focused on investigating the effect of a small interfering RNA (siRNA)-mediated decrease in fatty acid elongation on CRC cells’ survival and migration. In our study, the elongase 4 (ELOVL4) and elongase 6 (ELOVL6) genes were observed to be highly overexpressed in both the CRC tissue obtained from patients and the CRC cells cultured in vitro (HT-29 and WiDr cell lines). The use of the siRNAs for ELOVL4 and ELOVL6 reduced cancer cell proliferation and migration rates. These findings indicate that the altered elongation process decreased the survival of CRC cells, and in the future, fatty acid elongases can be potentially good targets in novel CRC therapy. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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17 pages, 7358 KiB

Open AccessArticle

Acetylcorynoline Induces Apoptosis and G2/M Phase Arrest through the c-Myc Signaling Pathway in Colon Cancer Cells

by Ye-Rin Park, Wona Jee, So-Mi Park, Seok-Woo Kim, Ji-Hoon Jung, Hyungsuk Kim, Kwan-Il Kim and Hyeung-Jin Jang

Int. J. Mol. Sci. 2023, 24(24), 17589; https://doi.org/10.3390/ijms242417589 - 18 Dec 2023

Cited by 1 | Viewed by 959

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and despite advances in treatment, survival rates are still low; therefore, the development of novel drugs is imperative. Acetylcorynoline (ACN) is derived from Corydalis ambigua Cham. et Schltdl tubers. The effect of ACN on colon cancer is still unknown. Therefore, we investigated its potential effects. Our data showed that ACN inhibited cell viability and proliferation. Moreover, ACN induced apoptosis and cell cycle arrest by inhibiting cell growth. In the present study, we hypothesized that ACN regulates c-Myc through CNOT2 or MID1IP1. ACN reduced the protein expression of oncogenic genes, decreased c-Myc half-life, and rapidly inhibited the serum stimulation response. Moreover, knockdown of CNOT2 and MID1IP1 with ACN increased apoptosis and further reduced the expression of oncogenes. In addition, ACN exhibited a synergistic effect with low-dose 5-fluorouracil (5-FU) and doxorubicin (Dox). Collectively, our data demonstrate that ACN inhibited c-Myc expression through CNOT2 and MID1IP1, and induced apoptosis. These findings indicate the potential of ACN as a therapeutic agent against colon cancer. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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15 pages, 2604 KiB

Open AccessArticle

Discovery of New Anti-Cancer Agents against Patient-Derived Sorafenib-Resistant Papillary Thyroid Cancer

by Yuna Kim, Hyeok Jun Yun, Kyung Hwa Choi, Chan Wung Kim, Jae Ha Lee, Raymond Weicker, Seok-Mo Kim and Ki Cheong Park

Int. J. Mol. Sci. 2023, 24(22), 16413; https://doi.org/10.3390/ijms242216413 - 16 Nov 2023

Cited by 1 | Viewed by 1010

Abstract

Thyroid cancer is the most well-known type of endocrine cancer that is easily treatable and can be completely cured in most cases. Nonetheless, anti-cancer drug-resistant metastasis or recurrence may occur and lead to the failure of cancer therapy, which eventually leads to the death of a patient with cancer. This study aimed to detect novel thyroid cancer target candidates based on validating and identifying one of many anti-cancer drug-resistant targets in patient-derived sorafenib-resistant papillary thyroid cancer (PTC). We focused on targeting the sarco/endoplasmic reticulum calcium ATPase (SERCA) in patient-derived sorafenib-resistant PTC cells compared with patient-derived sorafenib-sensitive PTC cells. We discovered novel SERCA inhibitors (candidates 33 and 36) by virtual screening. These candidates are novel SERCA inhibitors that lead to remarkable tumor shrinkage in a xenograft tumor model of sorafenib-resistant patient-derived PTC cells. These results are clinically valuable for the progression of novel combinatorial strategies that facultatively and efficiently target extremely malignant cancer cells, such as anti-cancer drug-resistant PTC cells. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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17 pages, 2879 KiB

Open AccessArticle

Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

by Hang-Seok Chang, Yonjung Kim, So Young Lee, Hyeok Jun Yun, Ho-Jin Chang and Ki Cheong Park

Int. J. Mol. Sci. 2023, 24(8), 7069; https://doi.org/10.3390/ijms24087069 - 11 Apr 2023

Cited by 4 | Viewed by 1589

Abstract

Thyroid cancer is generally curable and, in many cases, can be completely treated, although it can sometimes recur after cancer therapy. Papillary thyroid cancer (PTC) is known as one of the most general subtypes of thyroid cancer, which take up nearly 80% of whole thyroid cancer. However, PTC may develop anti-cancer drug resistance via metastasis or recurrence, making it practically incurable. In this study, we propose a clinical approach that identifies novel candidates based on target identification and validation of numerous survival-involved genes in human sorafenib-sensitive and -resistant PTC. Consequently, we recognized a sarco/endoplasmic reticulum calcium ATPase (SERCA) in human sorafenib-resistant PTC cells. Based on the present results, we detected novel SERCA inhibitor candidates 24 and 31 via virtual screening. These SERCA inhibitors showed remarkable tumor shrinkage in the sorafenib-resistant human PTC xenograft tumor model. These consequences would be clinically worthwhile for the development of a new combinatorial strategy that effectively targets incredibly refractory cancer cells, such as cancer stem cells and anti-cancer drug-resistant cells. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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15 pages, 3447 KiB

Open AccessArticle

Effects of Oncolytic Vaccinia Viruses Harboring Different Marine Lectins on Hepatocellular Carcinoma Cells

by Yanrong Zhou, Qianpeng Wang, Qi Ying, Xiaomei Zhang, Kan Chen, Ting Ye and Gongchu Li

Int. J. Mol. Sci. 2023, 24(4), 3823; https://doi.org/10.3390/ijms24043823 - 14 Feb 2023

Cited by 1 | Viewed by 1383

Abstract

Oncolytic viruses are being developed as novel strategies for cancer therapy. Our previous studies have shown that vaccinia viruses armed with marine lectins improved the antitumor efficacy in diverse cancer types. The objective of this study was to assess the cytotoxic effects of oncoVV harboring Tachypleus tridentatus lectin (oncoVV-TTL), Aphrocallistes vastus lectin (oncoVV-AVL), white-spotted charr lectin (oncoVV-WCL), and Asterina pectinifera lectin (oncoVV-APL) on HCC. Our data revealed that the effects of recombinant viruses on Hep-3B cells were oncoVV-AVL > oncoVV-APL > oncoVV-TTL > oncoVV-WCL; oncoVV-AVL showed stronger cytotoxicity than oncoVV-APL, while oncoVV-TTL/WCL had no effect on cell killing in Huh7 cells, and PLC/PRF/5 cells exhibited sensitivity to oncoVV-AVL/TTL but not to oncoVV-APL/WCL. The cytotoxicity of oncoVV-lectins could be enhanced by apoptosis and replication in a cell-type-dependent manner. Further research revealed that AVL may mediate various pathways, including MAPK, Hippo, PI3K, lipid metabolism, and androgen pathways through AMPK crosstalk, to promote oncoVV replication in HCC in a cell-dependent manner. OncoVV-APL replication could be affected by AMPK/Hippo/lipid metabolism pathways in Hep-3B cells, AMPK/Hippo/PI3K/androgen pathways in Huh7 cells, and AMPK/Hippo pathways in PLC/PRF/5 cells. OncoVV-WCL replication was also multi-mechanistic, which could be affected by AMPK/JNK/lipid metabolism pathways in Hep-3B cells, AMPK/Hippo/androgen pathways in Huh7 cells, and AMPK/JNK/Hippo pathways in PLC/PRF/5 cells. In addition, AMPK and lipid metabolism pathways may play critical roles in oncoVV-TTL replication in Hep-3B cells, and oncoVV-TTL replication in Huh7 cells may depend on AMPK/PI3K/androgen pathways. This study provides evidence for the application of oncolytic vaccinia viruses in hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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21 pages, 13227 KiB

Open AccessArticle

Targeting Lysosomes in Colorectal Cancer: Exploring the Anticancer Activity of a New Benzo[a]phenoxazine Derivative

by João C. C. Ferreira, Sara Granja, Ana F. Almeida, Fátima Baltazar, M. Sameiro T. Gonçalves, Ana Preto and Maria João Sousa

Int. J. Mol. Sci. 2023, 24(1), 614; https://doi.org/10.3390/ijms24010614 - 29 Dec 2022

Cited by 5 | Viewed by 1944

Abstract

Colorectal cancer (CRC) has been ranked as one of the cancer types with a higher incidence and one of the most mortal. There are limited therapies available for CRC, which urges the finding of intracellular targets and the discovery of new drugs for innovative therapeutic approaches. In addition to the limited number of effective anticancer agents approved for use in humans, CRC resistance and secondary effects stemming from classical chemotherapy remain a major clinical problem, reinforcing the need for the development of novel drugs. In the recent years, the phenoxazines derivatives, Nile Blue analogues, have been shown to possess anticancer activity, which has created interest in exploring the potential of these compounds as anticancer drugs. In this context, we have synthetized and evaluated the anticancer activity of different benzo[a]phenoxazine derivatives for CRC therapy. Our results revealed that one particular compound, BaP1, displayed promising anticancer activity against CRC cells. We found that BaP1 is selective for CRC cells and reduces cell proliferation, cell survival, and cell migration. We observed that the compound is associated with reactive oxygen species (ROS) generation, accumulates in the lysosomes, and leads to lysosomal membrane permeabilization, cytosolic acidification, and apoptotic cell death. In vivo results using a chicken embryo choriollantoic membrane (CAM) assay showed that BaP1 inhibits tumor growth, angiogenesis, and tumor proliferation. These observations highlight that BaP1 as a very interesting agent to disturb and counteract the important roles of lysosomes in cancer and suggests BaP1 as a promising candidate to be exploited as new anticancer lysosomal-targeted agent, which uses lysosome membrane permeabilization (LMP) as a therapeutic approach in CRC. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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Review

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16 pages, 1126 KiB

Open AccessReview

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant

by Rafael Coveñas, Francisco D. Rodríguez, Prema Robinson and Miguel Muñoz

Int. J. Mol. Sci. 2023, 24(21), 15936; https://doi.org/10.3390/ijms242115936 - 03 Nov 2023

Cited by 2 | Viewed by 950

Abstract

The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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20 pages, 3509 KiB

Open AccessReview

Harnessing the Potential of Non-Apoptotic Cell Death Processes in the Treatment of Drug-Resistant Melanoma

by Linyinxue Dong, Ceeane Paul Dagoc Vargas, Xuechen Tian, Xiayu Chu, Chenqi Yin, Aloysius Wong and Yixin Yang

Int. J. Mol. Sci. 2023, 24(12), 10376; https://doi.org/10.3390/ijms241210376 - 20 Jun 2023

Cited by 3 | Viewed by 2221

Abstract

Melanoma is a highly malignant skin cancer that is known for its resistance to treatments. In recent years, there has been significant progress in the study of non-apoptotic cell death, such as pyroptosis, ferroptosis, necroptosis, and cuproptosis. This review provides an overview of the mechanisms and signaling pathways involved in non-apoptotic cell death in melanoma. This article explores the interplay between various forms of cell death, including pyroptosis, necroptosis, ferroptosis, and cuproptosis, as well as apoptosis and autophagy. Importantly, we discuss how these non-apoptotic cell deaths could be targeted as a promising therapeutic strategy for the treatment of drug-resistant melanoma. This review provides a comprehensive overview of non-apoptotic processes and gathers recent experimental evidence that will guide future research and eventually the creation of treatment strategies to combat drug resistance in melanoma. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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41 pages, 25173 KiB

Open AccessReview

Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies

by Manuel Lisardo Sánchez, Francisco D. Rodríguez and Rafael Coveñas

Int. J. Mol. Sci. 2023, 24(12), 9962; https://doi.org/10.3390/ijms24129962 - 09 Jun 2023

Cited by 5 | Viewed by 2901

Abstract

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system’s high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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19 pages, 597 KiB

Open AccessReview

Clinical Value of Circulating miRNA in Diagnosis, Prognosis, Screening and Monitoring Therapy of Pancreatic Ductal Adenocarcinoma–A Review of the Literature

by Jakub Wnuk, Joanna Katarzyna Strzelczyk and Iwona Gisterek

Int. J. Mol. Sci. 2023, 24(6), 5113; https://doi.org/10.3390/ijms24065113 - 07 Mar 2023

Cited by 5 | Viewed by 1954

Abstract

Pancreatic cancer (PC) is considered to be the seventh most common cause of cancer-related deaths. The number of deaths caused by PC is estimated to increase in the future. An early diagnosis of PC is crucial for improving treatment outcomes. The most common histopathological subtype of PC is pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miRNAs)—which are endogenous non-coding RNAs involved in the posttranscriptional regulation of multiple gene expression—constitute useful diagnostic and prognostic biomarkers in various neoplasms, including PDAC. Circulating miRNAs detected in a patient’s serum or plasma are drawing more and more attention. Hence, this review aims at evaluating the clinical value of circulating miRNA in the screening, diagnosis, prognosis and monitoring of pancreatic ductal adenocarcinoma therapy. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics)

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