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Contribution of Cancer-Targeting Drugs toward Faster Clinical Application

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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 September 2021) | Viewed by 26038

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Special Issue Editors

Prof. Dr. Sungpil Yoon

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Guest Editor

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Interests: drug-resistant cancer; poor prognostic cancer; cancer metabolism; transcriptional regulation of cancer; drug repositioning; combination therapy; drugs for faster clinical application
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Hyung Sik Kim

E-Mail Website
Guest Editor

School of Pharmacy, Sungkyunkwan University, Korea
Interests: drug-resistant cancer; poor prognostic cancer; cancer metabolism; transcriptional regulation of cancer; drug repositioning; combination therapy; drugs for faster clinical application

Special Issue Information

Dear Colleagues,

Various cancer-targeting drugs (synthesized small molecules, natural products, antibodies, etc.) have been developed; these include: 1. general chemotherapeutic drugs that inhibit cell division and growth, 2. specific protein-targeting drugs that block overexpressed growth signaling, the abnormal production of ATP energy, or cancer-generated angiogenesis, and 3. cellular immunotherapeutic drugs with an enhanced attack on cancer cells.

However, in many cases, cancer cells have developed resistance to current cancer-targeting drugs. Drug-resistant cancers (P-glycoprotein overexpression or mutations in the growth signaling pathways, apoptotic pathways, or repair system), metastatic cancers, advanced-stage cancers (e.g., ovarian or pancreatic), or stem cell-like cancers are difficult to treat using the currently available cancer-targeting drugs. Therefore, it is important to improve the existing drugs or generate novel therapeutic options to overcome the failure of current cancer-targeting drugs. Identifying the mechanisms or therapeutic options (single drug or combination therapy) for targeting cancer cells that would overcome the inefficiencies of current cancer-targeting drugs could lead to better treatment options for patients with cancers that are resistant to the available cancer-targeting drugs.

In this Research Topic, we aim to identify and investigate the novel applications of cancer-targeting drugs, including 1. products derived from original drugs, 2. drug repositioning, 3. experimental drugs soon to be available for testing in clinical trials, and 4. plant extracts or natural products. In our investigations, we also plan to include the pharmacokinetics and pharmacodynamics of combination drug treatments offering improvements over current therapies.

We expect that our findings will encourage the faster initiation of clinical trials as well as therapeutic application.

Prof. Dr. Sungpil Yoon
Prof. Dr. Hyung Sik Kim
Guest Editors

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Keywords

anti-cancer drug
chemotherapy
molecular targeting
immunotherapy
co-treatment
low toxicity
resistant cancer
metastasis
late stage cancer
cancer stem cell

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Published Papers (7 papers)

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Research

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15 pages, 5190 KiB

Open AccessArticle

JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells

by Yunmoon Oh, Jin-Sol Lee, Ji Sun Lee, Jae Hyeon Park, Hyung Sik Kim and Sungpil Yoon

Int. J. Mol. Sci. 2022, 23(9), 4597; https://doi.org/10.3390/ijms23094597 - 21 Apr 2022

Cited by 16 | Viewed by 2550

Abstract

P-glycoprotein (P-gp) overexpression is one of the major mechanisms of multidrug resistance (MDR). Previously, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. In this study, we assessed the cytotoxic effects of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC). However, fedratinib-induced cytotoxicity was little effect on VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were used to further investigate fedratinib’s mechanism of action in VIC-treated KBV20C cells. We found that fedratinib reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC–fedratinib-co-treated cells resulted from the upregulation of p21 and the DNA damaging marker pH2AX. Compared with dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells showed two-fold higher P-gp-inhibitory activity, indicating that VIC–fedratinib sensitization is dependent on the activity of fedratinib. Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC–fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC–CEP-33779 or VIC–NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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13 pages, 3648 KiB

Open AccessArticle

High-Throughput 3D Tumor Spheroid Array Platform for Evaluating Sensitivity of Proton-Drug Combinations

by Dong Woo Lee, Jung Eun Kim, Ga-Haeng Lee, Arang Son, Hee Chul Park, Dongryul Oh, Kwanghyun Jo and Changhoon Choi

Int. J. Mol. Sci. 2022, 23(2), 587; https://doi.org/10.3390/ijms23020587 - 6 Jan 2022

Cited by 7 | Viewed by 3612

Abstract

Proton beam therapy (PBT) is a critical treatment modality for head and neck squamous cell carcinoma (HNSCC). However, not much is known about drug combinations that may improve the efficacy of PBT. This study aimed to test the feasibility of a three-dimensional (3D) tumor-spheroid-based high-throughput screening platform that could assess cellular sensitivity against PBT. Spheroids of two HNSCC cell lines—Fadu and Cal27—cultured with a mixture of Matrigel were arrayed on a 384-pillar/well plate, followed by exposure to graded doses of protons or targeted drugs including olaparib at various concentrations. Calcein staining of HNSCC spheroids revealed a dose-dependent decrease in cell viability for proton irradiation or multiple targeted drugs, and provided quantitative data that discriminated the sensitivity between the two HNSCC cell lines. The combined effect of protons and olaparib was assessed by calculating the combination index from the survival rates of 4 × 4 matrices, showing that Cal27 spheroids had greater synergy with olaparib than Fadu spheroids. In contrast, adavosertib did not synergize with protons in both spheroids. Taken together, we demonstrated that the 3D pillar/well array platform was a useful tool that provided rapid, quantitative data for evaluating sensitivity to PBT and drug combinations. Our results further supported that administration of the combination of PBT and olaparib may be an effective treatment strategy for HNSCC patients. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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13 pages, 4452 KiB

Open AccessArticle

Bazedoxifene, a GP130 Inhibitor, Modulates EMT Signaling and Exhibits Antitumor Effects in HPV-Positive Cervical Cancer

by Leekyung Kim, Sun-Ae Park, Hyemin Park, Heejung Kim and Tae-Hwe Heo

Int. J. Mol. Sci. 2021, 22(16), 8693; https://doi.org/10.3390/ijms22168693 - 13 Aug 2021

Cited by 18 | Viewed by 2788

Abstract

Persistent HPV (Human Papillomavirus) infection is the primary cause of cervical cancer. Despite the development of the HPV vaccine to prevent infections, cervical cancer is still a fatal malignant tumor and metastatic disease, and it is often difficult to treat, so a new treatment strategy is needed. The FDA-approved drug Bazedoxifene is a novel inhibitor of protein–protein interactions between IL-6 and GP130. Multiple ligand simultaneous docking and drug repositioning approaches have demonstrated that an IL-6/GP130 inhibitor can act as a selective estrogen modulator. However, the molecular basis for GP130 activation in cervical cancer remains unclear. In this study, we investigated the anticancer properties of Bazedoxifene in HPV-positive cervical cancer cells. In vitro and in vivo experiments showed that Bazedoxifene inhibited cell invasion, migration, colony formation, and tumor growth in cervical cancer cells. We also confirmed that Bazedoxifene inhibits the GP130/STAT3 pathway and suppresses the EMT (Epithelial-mesenchymal transition) sub-signal. Thus, these data not only suggest a molecular mechanism by which the GP130/STAT3 pathway may promote cancer, but also may provide a basis for cervical cancer replacement therapy. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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21 pages, 7008 KiB

Open AccessArticle

Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

by Deniz Caylioglu, Rieke Johanna Meyer, Dana Hellmold, Carolin Kubelt, Michael Synowitz and Janka Held-Feindt

Int. J. Mol. Sci. 2021, 22(7), 3606; https://doi.org/10.3390/ijms22073606 - 30 Mar 2021

Cited by 9 | Viewed by 2439

Abstract

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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16 pages, 3113 KiB

Open AccessArticle

Loss of FADD and Caspases Affects the Response of T-Cell Leukemia Jurkat Cells to Anti-Cancer Drugs

by Zuzana Mrkvová, Michaela Portešová and Iva Slaninová

Int. J. Mol. Sci. 2021, 22(5), 2702; https://doi.org/10.3390/ijms22052702 - 7 Mar 2021

Cited by 8 | Viewed by 3004

Abstract

Programmed cell death (PCD) pathways play a crucial role in the response of cancer cells to treatment. Their dysregulation is one of the cancer hallmarks and one of the reasons of drug resistance. Here, we studied the significance of the individual members of PCD signaling pathways in response to treatment with common anti-cancer drugs using the T-cell leukemia Jurkat cells with single or double knockouts of necroptosis and/or apoptosis genes. We identified apoptosis as the primary cell death pathway upon anti-cancer drugs treatment. The cells with knocked out either Fas-associated protein with death domain (FADD) or all executioner caspases were resistant. This resistance could be partially overcome by induction of RIP1-dependent necroptosis through TNFR1 activation using combined treatment with TNF-α and smac mimetic (LCL161). RIP1 was essential for cellular response to TNF-α and smac mimetic, but dispensable for the response to anti-cancer drugs. Here, we demonstrated the significance of FADD and executioner caspases in carrying out programmed cell death upon anti-cancer drug treatments and the ability of combined treatment with TNF-α and smac mimetic to partially overcome drug resistance of FADD and/or CASP3/7/6-deficient cells via RIP1-dependent necroptosis. Thus, a combination of TNF-α and smac mimetic could be a suitable strategy for overcoming resistance to therapy in cells unable to trigger apoptosis. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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Review

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16 pages, 2930 KiB

Open AccessReview

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

by Soonsil Hyun and Dongyun Shin

Int. J. Mol. Sci. 2021, 22(22), 12142; https://doi.org/10.3390/ijms222212142 - 9 Nov 2021

Cited by 15 | Viewed by 7739

Abstract

Drug resistance continues to be a major problem associated with cancer treatment. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the activity of KRAS. However, the RAS protein is still one of the most prominent targets for drugs in cancer treatment. Recently, novel targeted protein degradation (TPD) strategies, such as proteolysis-targeting chimeras, have been developed to render “undruggable” targets druggable and overcome drug resistance and mutation problems. In this study, we discuss small-molecule inhibitors, TPD-based small-molecule chemicals for targeting RAS pathway proteins, and their potential applications for treating KRAS-mutant cancers. Novel TPD strategies are expected to serve as promising therapeutic methods for treating tumor patients with KRAS mutations. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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24 pages, 547 KiB

Open AccessReview

Synthetic Retinoids as Potential Therapeutics in Prostate Cancer—An Update of the Last Decade of Research: A Review

by Przemysław Hałubiec, Agnieszka Łazarczyk, Oskar Szafrański, Torsten Bohn and Joanna Dulińska-Litewka

Int. J. Mol. Sci. 2021, 22(19), 10537; https://doi.org/10.3390/ijms221910537 - 29 Sep 2021

Cited by 6 | Viewed by 2519

Abstract

Prostate cancer (PC) is the second most common tumor in males. The search for appropriate therapeutic options against advanced PC has been in process for several decades. Especially after cessation of the effectiveness of hormonal therapy (i.e., emergence of castration-resistant PC), PC management options have become scarce and the prognosis is poor. To overcome this stage of disease, an array of natural and synthetic substances underwent investigation. An interesting and promising class of compounds constitutes the derivatives of natural retinoids. Synthesized on the basis of the structure of retinoic acid, they present unique and remarkable properties that warrant their investigation as antitumor drugs. However, there is no up-to-date compilation that consecutively summarizes the current state of knowledge about synthetic retinoids with regard to PC. Therefore, in this review, we present the results of the experimental studies on synthetic retinoids conducted within the last decade. Our primary aim is to highlight the molecular targets of these compounds and to identify their potential promise in the treatment of PC. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application)

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