International Journal of Molecular Sciences

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Open AccessEditorial

Contribution of Cancer-Targeting Drugs toward Faster Clinical Application

by Sungpil Yoon and Hyung Sik Kim

Int. J. Mol. Sci. 2022, 23(12), 6445; https://doi.org/10.3390/ijms23126445 - 9 Jun 2022

Cited by 4 | Viewed by 1252

Abstract

With advances in cancer-targeting therapeutic strategies, cancer cells have developed drug resistance [...] Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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Research

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16 pages, 2606 KiB

Open AccessArticle

Cantharidin and Its Analogue Norcantharidin Inhibit Metastasis—Inducing Genes S100A4 and MACC1

by Paul Curtis Schöpe, Viktoria Zinnow, Muhammad Ahtisham Ishfaq, Janice Smith, Pia Herrmann, Robert H. Shoemaker, Wolfgang Walther and Ulrike Stein

Int. J. Mol. Sci. 2023, 24(2), 1179; https://doi.org/10.3390/ijms24021179 - 7 Jan 2023

Cited by 3 | Viewed by 2065

Abstract

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. In addition, metastasis directly causes up to 90% of all CRC deaths, highlighting the metastatic burden of the disease. Biomarkers such as S100A4 and MACC1 aid in identifying patients with [...] Read more.

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. In addition, metastasis directly causes up to 90% of all CRC deaths, highlighting the metastatic burden of the disease. Biomarkers such as S100A4 and MACC1 aid in identifying patients with a high risk of metastasis formation. High expression of S100A4 or MACC1 and to a greater extent the combination of both biomarkers is a predictor for metastasis and poor patient survival in CRC. MACC1 is a tumor-initiating and metastasis-promoting oncogene, whereas S100A4 has not been shown to initiate tumor formation but can, nevertheless, promote malignant tumor growth and metastasis formation. Cantharidin is a natural drug extracted from various blister beetle species, and its demethylated analogue norcantharidin has been shown in several studies to have an anti-cancer and anti-metastatic effect in different cancer entities such as CRC, breast cancer, and lung cancer. The impact of the natural compound cantharidin and norcantharidin on S100A4 and MACC1 gene expression, cancer cell migration, motility, and colony formation in vitro was tested. Here, for the first time, we have demonstrated that cantharidin and norcantharidin are transcriptional inhibitors of S100A4 and MACC1 mRNA expression, protein expression, and motility in CRC cells. Our results clearly indicate that cantharidin and, to a lesser extent, its analogue norcantharidin are promising compounds for efficient anti-metastatic therapy targeting the metastasis-inducing genes S100A4 and MACC1 for personalized medicine for cancer patients. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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18 pages, 12324 KiB

Open AccessArticle

Regorafenib and Ruthenium Complex Combination Inhibit Cancer Cell Growth by Targeting PI3K/AKT/ERK Signalling in Colorectal Cancer Cells

by Deepu Sharma, Fayyaz Rasool, Manjri Bharti, Komal M. Vyas and Sri Krishna Jayadev Magani

Int. J. Mol. Sci. 2023, 24(1), 686; https://doi.org/10.3390/ijms24010686 - 30 Dec 2022

Cited by 1 | Viewed by 1971

Abstract

Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths annually. As in all other cancers, kinases are one of the major enzymes that play an essential [...] Read more.

Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths annually. As in all other cancers, kinases are one of the major enzymes that play an essential role in the incidence and progression of CRC. Thus, using multi-kinase inhibitors is one of the therapeutic strategies used to counter advanced-stage CRC. Regorafenib is an FDA-approved drug in the third-line therapy of refractory metastatic colorectal cancer. Acquired resistance to cancers and higher toxicity of these drugs are disadvantages to the patients. To counter this, combination therapy is used as a strategy where a minimal dose of drugs can be used to get a higher efficacy and reduce drug resistance development. Ruthenium-based compounds are observed to be a potential alternative to platinum-based drugs due to their significant safety and effectiveness. Formerly, our lab reported Ru-1, a ruthenium-based compound, for its anticancer activity against multiple cancer cells, such as HepG2, HCT116, and MCF7. This study evaluates Ru-1′s activity against regorafenib-resistant HCT116 cells and as a combination therapeutic with regorafenib. Meanwhile, the mechanism of the effect of Ru-1 alone and with regorafenib as a combination is still unknown. In this study, we tested a drug combination (Ru-1 and regorafenib) against a panel of HT29, HCT116, and regorafenib-resistant HCT116 cells. The combination showed a synergistic inhibitory activity. Several mechanisms underlying these numerous synergistic activities, such as anti-proliferative efficacy, indicated that the combination exhibited potent cytotoxicity and enhanced apoptosis induction. Disruption of mitochondrial membrane potential increased intracellular ROS levels and decreased migratory cell properties were observed. The combination exhibited its activity by regulating PI3K/Akt and p38 MAP kinase signalling. This indicates that the combination of REG/Ru-1 targets cancer cells by modulating the PI3K/Akt and ERK signalling. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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15 pages, 2101 KiB

Open AccessArticle

Terconazole, an Azole Antifungal Drug, Increases Cytotoxicity in Antimitotic Drug-Treated Resistant Cancer Cells with Substrate-Specific P-gp Inhibitory Activity

by Ji Sun Lee, Yunmoon Oh, Jae Hyeon Park, So Young Kyung, Hyung Sik Kim and Sungpil Yoon

Int. J. Mol. Sci. 2022, 23(22), 13809; https://doi.org/10.3390/ijms232213809 - 9 Nov 2022

Cited by 5 | Viewed by 1436

Abstract

Azole antifungal drugs have been shown to enhance the cytotoxicity of antimitotic drugs in P-glycoprotein (P-gp)-overexpressing-resistant cancer cells. Herein, we examined two azole antifungal drugs, terconazole (TCZ) and butoconazole (BTZ), previously unexplored in resistant cancers. We found that both TCZ and BTZ increased [...] Read more.

Azole antifungal drugs have been shown to enhance the cytotoxicity of antimitotic drugs in P-glycoprotein (P-gp)-overexpressing-resistant cancer cells. Herein, we examined two azole antifungal drugs, terconazole (TCZ) and butoconazole (BTZ), previously unexplored in resistant cancers. We found that both TCZ and BTZ increased cytotoxicity in vincristine (VIC)-treated P-gp-overexpressing drug-resistant KBV20C cancer cells. Following detailed analysis, low-dose VIC + TCZ exerted higher cytotoxicity than co-treatment with VIC + BTZ. Furthermore, we found that VIC + TCZ could increase apoptosis and induce G2 arrest. Additionally, low-dose TCZ could be combined with various antimitotic drugs to increase their cytotoxicity in P-gp-overexpressing antimitotic drug-resistant cancer cells. Moreover, TCZ exhibited P-gp inhibitory activity, suggesting that the inhibitory activity of P-gp plays a role in sensitization afforded by VIC + TCZ co-treatment. We also evaluated the cytotoxicity of 12 azole antifungal drugs at low doses in drug-resistant cancer cells. VIC + TCZ, VIC + itraconazole, and VIC + posaconazole exhibited the strongest cytotoxicity in P-gp-overexpressing KBV20C and MCF-7/ADR-resistant cancer cells. These drugs exerted robust P-gp inhibitory activity, accompanied by calcein-AM substrate efflux. Given that azole antifungal drugs have long been used in clinics, our results, which reposition azole antifungal drugs for treating P-gp-overexpressing-resistant cancer, could be employed to treat patients with drug-resistant cancer rapidly. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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15 pages, 3626 KiB

Open AccessArticle

PRMT7 Inhibitor SGC8158 Enhances Doxorubicin-Induced DNA Damage and Its Cytotoxicity

by Ahyeon Jeong, Yena Cho, Minkyeong Cho, Gyu-Un Bae, Dae-Geun Song, Su-Nam Kim and Yong Kee Kim

Int. J. Mol. Sci. 2022, 23(20), 12323; https://doi.org/10.3390/ijms232012323 - 14 Oct 2022

Cited by 4 | Viewed by 2495

Abstract

Protein arginine methyltransferase 7 (PRMT7) regulates various cellular responses, including gene expression, cell migration, stress responses, and stemness. In this study, we investigated the biological role of PRMT7 in cell cycle progression and DNA damage response (DDR) by inhibiting PRMT7 activity with either [...] Read more.

Protein arginine methyltransferase 7 (PRMT7) regulates various cellular responses, including gene expression, cell migration, stress responses, and stemness. In this study, we investigated the biological role of PRMT7 in cell cycle progression and DNA damage response (DDR) by inhibiting PRMT7 activity with either SGC8158 treatment or its specific siRNA transfection. Suppression of PRMT7 caused cell cycle arrest at the G₁ phase, resulting from the stabilization and subsequent accumulation of p21 protein. In addition, PRMT7 activity is closely associated with DNA repair pathways, including both homologous recombination and non-homologous end-joining. Interestingly, SGC8158, in combination with doxorubicin, led to a synergistic increase in both DNA damage and cytotoxicity in MCF7 cells. Taken together, our data demonstrate that PRMT7 is a critical modulator of cell growth and DDR, indicating that it is a promising target for cancer treatment. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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13 pages, 3356 KiB

Open AccessArticle

Low-Dose Rifabutin Increases Cytotoxicity in Antimitotic-Drug-Treated Resistant Cancer Cells by Exhibiting Strong P-gp-Inhibitory Activity

by Ji Sun Lee, Yunmoon Oh, Hyung Sik Kim and Sungpil Yoon

Int. J. Mol. Sci. 2022, 23(13), 7383; https://doi.org/10.3390/ijms23137383 - 2 Jul 2022

Cited by 5 | Viewed by 2176

Abstract

The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the cytotoxicity of various antimitotic drugs, such as vincristine (VIC), to P-glycoprotein (P-gp)-overexpressing antimitotic-drug-resistant KBV20C cells. Rifabutin was also found [...] Read more.

The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the cytotoxicity of various antimitotic drugs, such as vincristine (VIC), to P-glycoprotein (P-gp)-overexpressing antimitotic-drug-resistant KBV20C cells. Rifabutin was also found to exert high levels of P-gp-inhibitory activity at 4 and 24 h posttreatment, suggesting that the cytotoxicity of VIC + rifabutin was mainly due to the direct binding of rifabutin to P-gp and the reduction of VIC efflux by P-gp. The combination of VIC + rifabutin also increased early apoptosis, G2 arrest, and the DNA damaging marker, pH2AX protein. Interestingly, only the combination of VIC + rifabutin induced remarkable levels of cytotoxicity in resistant KBV20C cells, whereas other combinations (VIC + rifampin, VIC + rifapentine, and VIC + rifaximin) induced less cytotoxicity. Such finding suggests that rifabutin specifically increases the cytotoxicity of VIC in KBV20C cells, independent of the toxic effect of the ansamycin antibiotic. Only rifabutin had high P-gp-inhibitory activity, which suggests that its high P-gp-inhibitory activity led to the increased cytotoxicity of VIC + rifabutin. As rifabutin has long been used in the clinic, repositioning this drug for P-gp-overexpressing resistant cancer could increase the availability of treatments for patients with drug-resistant cancer. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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12 pages, 1808 KiB

Open AccessArticle

Hybrid Self-Assembling Nanoparticles Encapsulating Zoledronic Acid: A Strategy for Fostering Their Clinical Use

by Marianna Abate, Lorena Scotti, Valeria Nele, Michele Caraglia, Marco Biondi, Giuseppe De Rosa, Carlo Leonetti, Virginia Campani, Silvia Zappavigna and Manuela Porru

Int. J. Mol. Sci. 2022, 23(9), 5138; https://doi.org/10.3390/ijms23095138 - 5 May 2022

Cited by 5 | Viewed by 1927

Abstract

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates or microRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixing of four components immediately before use. The self-assembling approach facilitates technology transfer, but the complexity of the SANP preparation [...] Read more.

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates or microRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixing of four components immediately before use. The self-assembling approach facilitates technology transfer, but the complexity of the SANP preparation protocol raises significant concerns in the clinical setting due to the high risk of human errors during the procedure. In this work, it was hypothesized that the SANP preparation protocol could be simplified by using freeze-dried formulations. An in-depth thermodynamic study was conducted on solutions of different cryoprotectants, namely sucrose, mannitol and trehalose, to test their ability to stabilize the produced SANPs. In addition, the ability of SANPs to deliver drugs after lyophilization was assessed on selected formulations encapsulating zoledronic acid in vitro in the T98G GBM cell line and in vivo in an orthotopic mouse model. Results showed that, after lyophilization optimization, freeze-dried SANPs encapsulating zoledronic acid could retain their delivery ability, showing a significant inhibition of T98G cell growth both in vitro and in vivo. Overall, these results suggest that freeze-drying may help boost the industrial development of SANPs for the delivery of drugs to the brain. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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Review

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13 pages, 995 KiB

Open AccessReview

First-Line Combination Treatment with Low-Dose Bipolar Drugs for ABCB1-Overexpressing Drug-Resistant Cancer Populations

by Sungpil Yoon and Hyung Sik Kim

Int. J. Mol. Sci. 2023, 24(9), 8389; https://doi.org/10.3390/ijms24098389 - 7 May 2023

Cited by 1 | Viewed by 2034

Abstract

Tumors include a heterogeneous population, of which a small proportion includes drug-resistant cancer (stem) cells. In drug-sensitive cancer populations, first-line chemotherapy reduces tumor volume via apoptosis. However, it stimulates drug-resistant cancer populations and finally results in tumor recurrence. Recurrent tumors are unresponsive to [...] Read more.

Tumors include a heterogeneous population, of which a small proportion includes drug-resistant cancer (stem) cells. In drug-sensitive cancer populations, first-line chemotherapy reduces tumor volume via apoptosis. However, it stimulates drug-resistant cancer populations and finally results in tumor recurrence. Recurrent tumors are unresponsive to chemotherapeutic drugs and are primarily drug-resistant cancers. Therefore, increased apoptosis in drug-resistant cancer cells in heterogeneous populations is important in first-line chemotherapeutic treatments. The overexpression of ABCB1 (or P-gp) on cell membranes is an important characteristic of drug-resistant cancer cells; therefore, first-line combination treatments with P-gp inhibitors could delay tumor recurrence. Low doses of bipolar drugs showed P-gp inhibitory activity, and their use as a combined therapy sensitized drug-resistant cancer cells. FDA-approved bipolar drugs have been used in clinics for a long period of time, and their toxicities are well reported. They can be easily applied as first-line combination treatments for targeting resistant cancer populations. To apply bipolar drugs faster in first-line combination treatments, knowledge of their complete information is crucial. This review discusses the use of low-dose bipolar drugs in sensitizing ABCB1-overexpressing, drug-resistant cancers. We believe that this review will contribute to facilitating first-line combination treatments with low-dose bipolar drugs for targeting drug-resistant cancer populations. In addition, our findings may aid further investigations into targeting drug-resistant cancer populations with low-dose bipolar drugs. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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21 pages, 2630 KiB

Open AccessReview

Innovative Anti-CD38 and Anti-BCMA Targeted Therapies in Multiple Myeloma: Mechanisms of Action and Resistance

by Danilo De Novellis, Raffaele Fontana, Valentina Giudice, Bianca Serio and Carmine Selleri

Int. J. Mol. Sci. 2023, 24(1), 645; https://doi.org/10.3390/ijms24010645 - 30 Dec 2022

Cited by 5 | Viewed by 5557

Abstract

CD38 and B-cell maturation antigens (BCMAs) are prevalently expressed on neoplastic plasma cells in multiple myeloma (MM), making them ideal therapeutic targets. Anti-CD38 monoclonal antibodies, such as approved daratumumab and isatuximab, are currently the milestone in MM treatment because they induce plasma cell [...] Read more.

CD38 and B-cell maturation antigens (BCMAs) are prevalently expressed on neoplastic plasma cells in multiple myeloma (MM), making them ideal therapeutic targets. Anti-CD38 monoclonal antibodies, such as approved daratumumab and isatuximab, are currently the milestone in MM treatment because they induce plasma cell apoptosis and kill through several mechanisms, including antibody-dependent cellular cytotoxicity or phagocytosis. BCMA is considered an excellent target in MM, and three different therapeutic strategies are either already available in clinical practice or under investigation: antibody–drug conjugates, such as belantamab-mafodotin; bispecific T cell engagers; and chimeric antigen receptor-modified T cell therapies. Despite the impressive clinical efficacy of these new strategies in the treatment of newly diagnosed or multi-refractory MM patients, several mechanisms of resistance have already been described, including antigen downregulation, the impairment of antibody-dependent cell cytotoxicity and phagocytosis, T- and natural killer cell senescence, and exhaustion. In this review, we summarize the current knowledge on the mechanisms of action and resistance of anti-CD38 and anti-BCMA agents and their clinical efficacy and safety. Full article

(This article belongs to the Special Issue Contribution of Cancer-Targeting Drugs toward Faster Clinical Application 2.0)

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