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24 pages, 3599 KiB

Open AccessArticle

Complementary Treatment of Breast Cancer Cells with Different Metastatic Potential with Iscador Qu in the Presence of Clinically Approved Anticancer Drugs

by Ivan Iliev, Iana Tsoneva, Aleksandrina Nesheva, Galya Staneva, Bozhil Robev, Albena Momchilova and Biliana Nikolova

Curr. Issues Mol. Biol. 2024, 46(11), 12457-12480; https://doi.org/10.3390/cimb46110740 - 5 Nov 2024

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Abstract

European mistletoe extract (Iscador Qu) has been studied for decades, but it has not ceased to arouse scientific interest. The purpose was to investigate the impact of Iscador Qu on the antiproliferative potential of 11 standard chemotherapeutic agents on two breast cancer cell [...] Read more.

European mistletoe extract (Iscador Qu) has been studied for decades, but it has not ceased to arouse scientific interest. The purpose was to investigate the impact of Iscador Qu on the antiproliferative potential of 11 standard chemotherapeutic agents on two breast cancer cell lines: MCF-7 low-metastatic and MDA-MB-231 high-metastatic and control cell lines (MCF-10A). MTT-dye reduction assay, FACS analysis, and PI staining were utilized. The most promising combinations acting against the MDA-MB-231 cell line were observed upon the simultaneous application of Iscador Qu (80 µg/mL) and Docetaxel, with 4-fold reduction in IC₅₀. An antagonistic effect was found under treatment with Cisplatin and Iscador Qu (1.5-fold increase in IC₅₀). The response of the low-metastatic breast cancer cell line MCF-7 to the tested combinations was different compared to the high-metastatic one. The most pronounced cytotoxic effect was found for the combination of Oxaliplatin and Iscador Qu (20 µg/mL) (5.2-fold IC₅₀ reduction). An antagonistic effect for MCF-7 line was also observed when combinations with Olaparib and Tamoxifen were applied. This in vitro study offers new combinations between Iscador Qu and standard chemotherapeutic agents that hold great promise in establishing breast cancer therapeutic protocols compared to traditional monotherapies. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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20 pages, 10682 KiB

Open AccessArticle

Comparative Molecular Docking of Apigenin and Luteolin versus Conventional Ligands for TP-53, pRb, APOBEC3H, and HPV-16 E6: Potential Clinical Applications in Preventing Gynecological Malignancies

by Momir Dunjic, Stefano Turini, Lazar Nejkovic, Nenad Sulovic, Sasa Cvetkovic, Marija Dunjic, Katarina Dunjic and Dina Dolovac

Curr. Issues Mol. Biol. 2024, 46(10), 11136-11155; https://doi.org/10.3390/cimb46100661 - 3 Oct 2024

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Abstract

This study presents a comparative analysis of molecular docking data, focusing on the binding interactions of the natural compounds apigenin and luteolin with the proteins TP-53, pRb, and APOBEC, in comparison to conventional pharmacological ligands. Advanced bioinformatics techniques were employed to evaluate and [...] Read more.

This study presents a comparative analysis of molecular docking data, focusing on the binding interactions of the natural compounds apigenin and luteolin with the proteins TP-53, pRb, and APOBEC, in comparison to conventional pharmacological ligands. Advanced bioinformatics techniques were employed to evaluate and contrast binding energies, showing that apigenin and luteolin demonstrate significantly higher affinities for TP-53, pRb, and APOBEC, with binding energies of −6.9 kcal/mol and −6.6 kcal/mol, respectively. These values suggest strong potential for therapeutic intervention against HPV-16. Conventional ligands, by comparison, exhibited lower affinities, with energies ranging from −4.5 to −5.5 kcal/mol. Additionally, protein–protein docking simulations were performed to assess the interaction between HPV-16 E6 oncoprotein and tumor suppressors TP-53 and pRb, which revealed high binding energies around −976.7 kcal/mol, indicative of their complex interaction. A conversion formula was applied to translate these protein–protein interaction energies to a comparable scale for non-protein interactions, further underscoring the superior binding potential of apigenin and luteolin. These findings highlight the therapeutic promise of these natural compounds in preventing HPV-16-induced oncogenesis, warranting further experimental validation for clinical applications. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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10 pages, 1746 KiB

Open AccessArticle

Association of Wild-Type TP53 with Downregulation of Lovastatin Sensitivity in Human Non-Small Cell Lung Cancer Cells

by Yu-Yao Chang, Tsung-Ying Yang and Gwo-Tarng Sheu

Curr. Issues Mol. Biol. 2024, 46(9), 10130-10139; https://doi.org/10.3390/cimb46090604 - 13 Sep 2024

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Abstract

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, and reduce cholesterol synthesis. They also have been demonstrated to improve prognosis in patients with various cancers, suggesting a potential anti-cancer effect of statins. However, there is no consensus on the [...] Read more.

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, and reduce cholesterol synthesis. They also have been demonstrated to improve prognosis in patients with various cancers, suggesting a potential anti-cancer effect of statins. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Docetaxel (DOC) is a microtubule-stabilizing agent currently used as a chemotherapeutic drug in several cancers, including lung cancer. Interestingly, the anti-cancer effects of either drug that are related to abnormal or wild-type TP53 gene have been implied. Therefore, the drug sensitivity of DOC and lovastatin in human lung cancer cells was evaluated. We found that H1355 (mutant TP53-E285K), CL1 (mutant TP53-R248W), and H1299 (TP53-null) human non-small cell lung cancer cells were more sensitive to lovastatin than A549 and H460 cells expressing wild-type TP53. Conversely, A549 and H460 cells showed higher sensitivity to DOC than H1299 and CL1 cells, as demonstrated by the MTT assay. When endogenous TP53 activity was inhibited by pifithrin-α in A549 and H460 cells, lovastatin sensitivities significantly increased, and cancer cell viabilities markedly reduced. These results indicate that TP53 status is associated with the anti-cancer effect of statins in human lung cancer cells. Mutated or null TP53 status is correlated with higher statin sensitivity. Furthermore, DOC-resistant H1299 (H1299/D8) cells showed significant sensitivity to lovastatin treatment compared to DOC-resistant A549 (A549/D16) cells, indicating a potential application of statins/chemotherapy combination therapy to control wild-type and abnormal TP53-containing human lung tumors. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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14 pages, 11623 KiB

Open AccessArticle

An In Vitro Investigation of the Antiproliferative and Antimetastatic Effects of Levosimendan: Potential Drug Repurposing for Cervical Cancer

by Zsuzsanna Schelz, Hiba F. Muddather, Fatemeh Sheihaki Jaski, Noémi Bózsity and István Zupkó

Curr. Issues Mol. Biol. 2024, 46(7), 6566-6579; https://doi.org/10.3390/cimb46070391 - 27 Jun 2024

Cited by 1 | Viewed by 1053

Abstract

Cervical cancer presents a significant challenge to the global health of women. Despite substantial advances in human papillomavirus (HPV)-related cervical cancer vaccines, non-HPV-related cervical cancer is still waiting novel therapeutic options. Drug repurposing has provided a promising approach to improve cancer therapy in [...] Read more.

Cervical cancer presents a significant challenge to the global health of women. Despite substantial advances in human papillomavirus (HPV)-related cervical cancer vaccines, non-HPV-related cervical cancer is still waiting novel therapeutic options. Drug repurposing has provided a promising approach to improve cancer therapy in recent years. Our study aimed to explore the potential in vitro antineoplastic effects of levosimendan on cervical cancer cells. The antiproliferative effects of levosimendan were investigated on cervical cancer cells using a standard MTT assay. Fluorescent double staining was performed to identify its ability to induce apoptosis and necrosis. The possible mechanism of action of levosimendan was explored using cell-cycle analysis. Furthermore, antimetastatic effects were investigated using a wound-healing assay and a Boyden chamber assay. Our results revealed that levosimendan exhibited the highest growth-inhibitory effect in the HPV-negative C33A cell line. However, the effects were modest compared to the standard agent, cisplatin. Cell-cycle analysis detected that levosimendan can induce cell-cycle arrest in C33A cells by increasing the G1 and G2/M phases, decreasing the S phase, and enhancing the hypodiploid subG1 population. Levosimendan inhibited cell migration and invasion in a concentration-dependent manner. As levosimendan showed antimetastatic efficacy, it could be considered for repurposing to contribute to overcoming resistance to therapy in cervical cancer. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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11 pages, 1319 KiB

Open AccessCommunication

Employing Bidirectional Two-Sample Mendelian Randomization Analysis to Verify the Potential of Polyunsaturated Fatty Acid Levels in the Prevention of Pancreatic Cancer

by Hao Sha and Weifeng Zhu

Curr. Issues Mol. Biol. 2024, 46(6), 6041-6051; https://doi.org/10.3390/cimb46060360 - 14 Jun 2024

Cited by 1 | Viewed by 1187

Abstract

Polyunsaturated fatty acids (PUFAs), specifically Omega-3 (FAω3) and docosahexaenoic acid (DHA), have been studied for their potential role in modulating pancreatic cancer (PC) risk. Although observational studies suggest a beneficial effect in reducing this risk, their findings are often limited by confounding variables [...] Read more.

Polyunsaturated fatty acids (PUFAs), specifically Omega-3 (FAω3) and docosahexaenoic acid (DHA), have been studied for their potential role in modulating pancreatic cancer (PC) risk. Although observational studies suggest a beneficial effect in reducing this risk, their findings are often limited by confounding variables and issues of reverse causation. This study used a two-way two-sample Mendelian randomization (MR) method to test the hypothesized genetic causal relationship between PUFAs and PC risk. Data from an extensive genome-wide association study (GWAS) were analyzed, focusing on FAω3 and FAω6 levels, their ratios, and DHA as variables and PC incidence as outcomes. This relationship was comprehensively evaluated using related MR methods, such as inverse variance weighting (IVW), MR Egger, and weighted median (WM). This study finds a significant negative correlation between FAω3 and DHA levels and PC risk, while FAω6 levels show no significant correlation. Interestingly, the ratio of FAω6 to FAω3 was positively associated with increased risk of PC. Neither the MR Egger nor the MR-PRESSO tests detected significant pleiotropy, nor did the Cochrane’s Q test show significant heterogeneity. Leave-one-out analyzes further confirmed the robustness of these results. Using MR analysis of two samples, this study provides genetic causal evidence that FAω3 and DHA levels reduce the risk of PC, whereas the ratio of FAω6 to FAω3 increases the risk of PC. These insights highlight the potential utility of supplementing FAω3 and DHA or altering PUFAs in developing PC prevention strategies. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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15 pages, 1635 KiB

Open AccessArticle

Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition

by Simone Mirabilii, Monica Piedimonte, Esmeralda Conte, Daniele Mirabilii, Francesca Maria Rossi, Riccardo Bomben, Antonella Zucchetto, Valter Gattei, Agostino Tafuri and Maria Rosaria Ricciardi

Curr. Issues Mol. Biol. 2024, 46(6), 5085-5099; https://doi.org/10.3390/cimb46060305 - 22 May 2024

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Abstract

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role [...] Read more.

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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17 pages, 5527 KiB

Open AccessArticle

The Biological Impact of Some Phosphonic and Phosphinic Acid Derivatives on Human Osteosarcoma

by Zakzak Khaled, Gheorghe Ilia, Claudia Watz, Ioana Macașoi, George Drăghici, Vasile Simulescu, Petru Eugen Merghes, Narcis Ion Varan, Cristina Adriana Dehelean, Lavinia Vlaia and Laurențiu Sima

Curr. Issues Mol. Biol. 2024, 46(5), 4815-4831; https://doi.org/10.3390/cimb46050290 - 15 May 2024

Cited by 3 | Viewed by 923

Abstract

Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to [...] Read more.

Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to outline its pharmaco-toxicological profile by employing two different in vitro human cell cultures (keratinocytes—HaCaT—and osteosarcoma SAOS-2 cells), employing different techniques (MTT assay, cell morphology assessment, LDH assay, Hoechst staining and RT-PCR). Additionally, the results obtained are compared with three commercially available phosphorus-containing compounds (P1, P2, P3). The results recorded for the newly developed compound (P4) revealed good biocompatibility (cell viability of 77%) when concentrations up to 5 mM were used on HaCaT cells for 24 h. Also, the HaCaT cultures showed no significant morphological alterations or gene modulation, thus achieving a biosafety profile even superior to some of the commercial products tested herein. Moreover, in terms of anti-osteosarcoma activity, 2-carboxyethylphenylphosphinic acid expressed promising activity on SAOS-2 monolayers, the cells showing viability of only 55%, as well as apoptosis features and important gene expression modulation, especially Bid downregulation. Therefore, the newly developed compound should be considered a promising candidate for further in vitro and in vivo research related to osteosarcoma therapy. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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14 pages, 6895 KiB

Open AccessCommunication

Stemness and Cell Cycle Regulators and Their Modulation by Retinoic Acid in Ewing Sarcoma

by Maria Eduarda Battistella, Natália Hogetop Freire, Bruno Toson, Matheus Dalmolin, Marcelo A. C. Fernandes, Isadora D. Tassinari, Mariane Jaeger, André T. Brunetto, Algemir L. Brunetto, Lauro Gregianin, Caroline Brunetto de Farias and Rafael Roesler

Curr. Issues Mol. Biol. 2024, 46(5), 3990-4003; https://doi.org/10.3390/cimb46050246 - 26 Apr 2024

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Abstract

Retinoic acid (RA) regulates stemness and differentiation in human embryonic stem cells (ESCs). Ewing sarcoma (ES) is a pediatric tumor that may arise from the abnormal development of ESCs. Here we show that RA impairs the viability of SK-ES-1 ES cells and affects [...] Read more.

Retinoic acid (RA) regulates stemness and differentiation in human embryonic stem cells (ESCs). Ewing sarcoma (ES) is a pediatric tumor that may arise from the abnormal development of ESCs. Here we show that RA impairs the viability of SK-ES-1 ES cells and affects the cell cycle. Cells treated with RA showed increased levels of p21 and its encoding gene, CDKN1A. RA reduced mRNA and protein levels of SRY-box transcription factor 2 (SOX2) as well as mRNA levels of beta III Tubulin (TUBB3), whereas the levels of CD99 increased. Exposure to RA reduced the capability of SK-ES-1 to form tumorspheres with high expression of SOX2 and Nestin. Gene expression of CD99 and CDKN1A was reduced in ES tumors compared to non-tumoral tissue, whereas transcript levels of SOX2 were significantly higher in tumors. For NES and TUBB3, differences between tumors and control tissue did not reach statistical significance. Low expression of CD99 and NES, and high expression of SOX2, were significantly associated with a poorer patient prognosis indicated by shorter overall survival (OS). Our results indicate that RA may display rather complex modulatory effects on multiple target genes associated with the maintenance of stem cell’s features versus their differentiation, cell cycle regulation, and patient prognosis in ES. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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Review

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16 pages, 1976 KiB

Open AccessReview

Targeting PGK1: A New Frontier in Breast Cancer Therapy Under Hypoxic Conditions

by Jiayong Cui, Shengjun Chai, Rui Liu and Guoshuang Shen

Curr. Issues Mol. Biol. 2024, 46(11), 12214-12229; https://doi.org/10.3390/cimb46110725 - 30 Oct 2024

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Abstract

Breast cancer represents one of the most prevalent malignant neoplasms affecting women, and its pathogenesis has garnered significant scholarly interest. Research indicates that the progression of breast cancer is intricately regulated by glucose metabolism. Under hypoxic conditions within the tumor microenvironment, breast cancer [...] Read more.

Breast cancer represents one of the most prevalent malignant neoplasms affecting women, and its pathogenesis has garnered significant scholarly interest. Research indicates that the progression of breast cancer is intricately regulated by glucose metabolism. Under hypoxic conditions within the tumor microenvironment, breast cancer cells generate ATP and essential biosynthetic precursors for growth via the glycolytic pathway. Notably, phosphoglycerate kinase 1 (PGK1) is intimately associated with the regulation of hypoxia-inducible factors in breast cancer and plays a crucial role in modulating glycolytic processes. Further investigation into the role of PGK1 in breast cancer pathogenesis is anticipated to identify novel therapeutic targets and strategies. This review consolidates current research on the regulation of glucose metabolism and the function of PGK1 in breast cancer within hypoxic conditions. It aims to offer a significant theoretical foundation for elucidating the mechanisms underlying breast cancer progression and metastasis, thereby facilitating the development of innovative treatment approaches. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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13 pages, 3443 KiB

Open AccessReview

The Role of Caspases in Melanoma Pathogenesis

by Agnieszka Szmurło, Klaudia Dopytalska, Michał Szczerba, Elżbieta Szymańska, Alicja Petniak, Marcin Kocki, Janusz Kocki and Irena Walecka

Curr. Issues Mol. Biol. 2024, 46(9), 9480-9492; https://doi.org/10.3390/cimb46090562 - 28 Aug 2024

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Abstract

Melanoma (malignant melanoma, MM) is an aggressive malignant skin cancer with an increasing incidence rate. The complete pathogenesis of MM in not clear. Due to DNA damage, mutations, dysregulation of growth factors, inactivation of tumor suppressor genes, and activation of oncogenes, excessive uncontrolled [...] Read more.

Melanoma (malignant melanoma, MM) is an aggressive malignant skin cancer with an increasing incidence rate. The complete pathogenesis of MM in not clear. Due to DNA damage, mutations, dysregulation of growth factors, inactivation of tumor suppressor genes, and activation of oncogenes, excessive uncontrolled growth of abnormal melanocytes occurs in melanomas. Caspases are a group of proteolytic enzymes that participate in several processes important in regulating mechanisms at the cellular level. They play a role in cell homeostasis and programmed cell death (apoptosis) and in the regulation of non-apoptotic cell death processes. Dysregulation of caspase activation plays a role in the etiology of cancers, including melanoma. Caspases can initiate and execute apoptosis and are involved in regulating cell death and controlling tumor growth. These enzymes also inhibit tumor growth by cleaving and inactivating proteins that are involved in cell proliferation and angiogenesis. Moreover, caspases are involved in the activation of immune processes through the processing and presentation of tumor antigens, which facilitates recognition of the tumor by the immune system. The role of caspases in melanoma is complex, and they may inhibit melanoma growth and progression. This work aims to review the current knowledge of the role of individual caspases in melanoma pathogenesis. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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15 pages, 2345 KiB

Open AccessReview

Medicinal Mushrooms in Metastatic Breast Cancer: What Is Their Therapeutic Potential as Adjuvant in Clinical Settings?

by Fabrizio De Luca, Elisa Roda, Paola Rossi and Maria Grazia Bottone

Curr. Issues Mol. Biol. 2024, 46(7), 7577-7591; https://doi.org/10.3390/cimb46070450 - 17 Jul 2024

Viewed by 2157

Abstract

Breast cancer (BC) is the most commonly diagnosed tumor, remaining one of the leading causes of morbidity and mortality in females worldwide, with the highest rates in Western countries. Among metastatic BC (MBC), triple-negative breast cancer (TNBC) is characterized by the lack of [...] Read more.

Breast cancer (BC) is the most commonly diagnosed tumor, remaining one of the leading causes of morbidity and mortality in females worldwide, with the highest rates in Western countries. Among metastatic BC (MBC), triple-negative breast cancer (TNBC) is characterized by the lack of expression of specific receptors, and differs from other subgroups of BC for its increased growth and fast spreading, with reduced treatment possibilities and a worse outcome. Actually, MBC patients are extremely prone to metastasis and consequent relapses, which affect distant target organs (e.g., brain, lung, bone and liver). Hence, the comprehension of biological mechanisms underlying the BC metastatization process is a key requirement to conceive/set up innovative medicinal strategies, with the goal to achieve long-lasting therapeutic efficacy, reducing adverse effects, and also ameliorating Quality of Life (QoL). Bioactive metabolites isolated from medicinal mushrooms (MMs) used as a supportive treatment, combined with conventional oncology, have recently gained wide interest. In fact, mounting evidence has revealed their peculiar promising immunomodulatory, anti-inflammatory and anticancer activities, even though these effects have to be further clarified. Among the group of most promising MMs are Lentinula edodes, Grifola frondosa, Ganoderma lucidum, Ophiocordyceps sinensis and Agaricus blazei, which are already employed in conventional cancer protocols in Asia and China. Recently, a growing number of studies have focused on the pharmacology and feasibility of MM-derived bioactive compounds as a novel valuable approach to propose an effective adjuvant therapy for MBC patients’ management. In this review, we summarized the current state of knowledge on the abovementioned MM-derived bioactive compounds and their therapeutic potential in clinical settings. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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18 pages, 3159 KiB

Open AccessReview

Changing the Landscape of Solid Tumor Therapy from Apoptosis-Promoting to Apoptosis-Inhibiting Strategies

by Razmik Mirzayans

Curr. Issues Mol. Biol. 2024, 46(6), 5379-5396; https://doi.org/10.3390/cimb46060322 - 28 May 2024

Cited by 3 | Viewed by 1355

Abstract

The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing [...] Read more.

The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that “in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong”. The message is clear: Novel therapeutic strategies with catchy names (e.g., synthetic “lethality”) have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the Nomenclature Committee on Cell Death (NCCD) and numerous other authors. These challenges include: The impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell “viability” and tumor growth delay studies in live animals) that score such pro-survival responses as “lethal” events. The studies outlined herein underscore the need for new directions in the management of solid tumors. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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