Despite significant breakthroughs in frontline cancer research and chemotherapy for hepatocellular carcinoma (HCC), many of the suggested drugs have high toxic side effects and resistance, limiting their clinical utility. Exploring potential therapeutic targets or novel combinations with fewer side effects is therefore crucial in combating this dreadful disease. The current study aims to use a novel combination of ponatinib and gossypol against the HepG2 cell line. Cell survival, FGF19/FGFR4, apoptotic and autophagic cell death, and synergistic drug interactions were assessed in response to increasing concentrations of ponatinib and/or gossypol treatment. Research revealed that ponatinib (1.25-40 μM) and gossypol (2.5-80 μM) reduced the viability of HepG2 cells in a way that was dependent on both time and dose. Ponatinib's anti-proliferation effectiveness was improved synergistically by gossypol and was associated with a rise in apoptotic cell death, cell cycle blockage during the G0/G1 phase, and suppression of the FGF19/FGFR4 axis. Furthermore, the ponatinib/gossypol combination lowered Bcl-2 and p-Akt while increasing active caspase-3, Beclin-1, p62, and LC3II. This combination, however, had no harm on normal hepatocytes. Overall, gossypol enhanced ponatinib's anticancer effects in HCC cells. Notably, this new combination appears to be potential adjuvant targeted chemotherapy, a discovery that warrants more clinical investigation, in the management of patients with HCC.

Gossypol, a polyphenolic compound predominantly derived from cotton plants, has garnered significant attention as a notable plant-derived bioactive compound with significant relevance in medicinal chemistry due to its diverse biological activities and potential therapeutic applications. Despite its inherent toxicity, gossypol exhibits insecticidal, antimicrobial, antiviral, antifertility, antiparasitic, anti-inflammatory, antioxidant, and anticancer properties. Furthermore, gossypol serves as a core molecule for synthesizing various derivatives, such as gossypol Schiff bases, gossypolone, and apogossypol, which are less toxic yet retain similar therapeutic benefits. The aim of this review is to provide a comprehensive overview of gossypol's diverse biological activities, with a particular focus on its anticancer potential, mechanisms of action, and recent advancements in its therapeutic applications. It highlights gossypol's wide-ranging biological activities, including its potent anticancer, antimicrobial, and antioxidant effects. Recent studies have shown promise in reducing gossypol's toxicity through the synthesis of derivatives, while advanced drug delivery methods, including nanocarriers, have been explored to enhance its therapeutic efficacy. Furthermore, gossypol has demonstrated significant synergistic potential when used in combination with conventional anticancer drugs, offering new avenues for cancer therapy.

Radiotherapy is a powerful tumor therapeutic strategy for gastric cancer patients. However, radioresistance is a major obstacle to kill cancer cells. Ginger (Zingiber officinale Roscoe) exerts a potential function in various cancers and is a noble combined therapy to overcome radioresistance in gastric cancer radiotherapy. In this study, we suggested that 8-shogaol, a monomethoxybenzene compound extracted from Zingiber officinale Roscoe, has an anti-cancer and anti-inflammatory activity. In lipopolysaccharide (LPS)-induced inflammatory murine models in vivo and in vitro, 8-shogaol suppressed LPS-mediated cytokine production, including COX-2, TNFα, IL-6, and IL-1β. In xenograft mouse models of AGS gastric cancer cell lines, 8-shogaol reduced tumor volume. In gastric cancer cell lines AGS and NCI-N87, 8-shogaol reduced cell viability and increased caspase-3 activity and cytotoxicity LDH. However, combined with Z-VAD-FMK, 8-shogaol blocked caspase-dependent apoptotic cell death. 8-Shogaol induced intracellular reactive oxygen species (ROS) production, intracellular calcium (Ca2+) release, and endoplasmic reticulum (ER) stress response via the PERK-CHOP signaling pathway. Thapsigargin (TG), an ER stressor, mediated synergistic apoptosis and cell death in 8-shogaol-treated AGS and NCI-N87 cell lines. Nevertheless, loss of PERK or CHOP function suppressed ER-stress-induced apoptosis and cell death in 8-shogaol-treated AGS and NCI-N87 cell lines. 8-Shogaol-induced NADPH oxidase 4 (NOX4) activation is related to ROS generation. However, NOX4 knockdown and ROS inhibitors DPI or NAC blocked ER-stress-induced apoptosis by suppressing the inhibition of cell viability and the enhance of caspase-3 activity, intracellular ROS activity, and cytotoxicity LDH in 8-shogaol-treated AGS and NCI-N87 cell lines. Radioresistant gastric cancer models (AGSR and NCI-N87R) were developed and combined with 8-shogaol and radiation (2 Gy) to overcome radioresistance via the upregulation of N-cadherin and vimentin and the downregulation of E-cadherin. Therefore, these results indicated that 8-shogaol is a novel combined therapeutic strategy in gastric cancer radiotherapy.

Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.

Cancer is a pernicious and pressing medical problem; moreover, it is a failure of multicellular morphogenesis that sheds much light on evolutionary developmental biology. Numerous classes of pharmacological agents have been considered as cancer therapeutics and evaluated as potential carcinogenic agents; however, these are spread throughout the primary literature. Here, we briefly review recent work on ion channel drugs as promising anti-cancer treatments and present a systematic review of the known cancer-relevant effects of 109 drugs targeting ion channels. The roles of ion channels in cancer are consistent with the importance of bioelectrical parameters in cell regulation and with the functions of bioelectric signaling in morphogenetic signals that act as cancer suppressors. We find that compounds that are well-known for having targets in the nervous system, such as voltage-gated ion channels, ligand-gated ion channels, proton pumps, and gap junctions are especially relevant to cancer. Our review suggests further opportunities for the repurposing of numerous promising candidates in the field of cancer electroceuticals.

Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2-/- zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2-/- zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2-/- zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.

Gossypol, a polyphenolic aldehyde derived from cottonseed plants, has seen a transformation in its pharmaceutical application from a male contraceptive to a candidate for cancer therapy. This shift is supported by its recognized antitumor properties, which have prompted its investigation in the treatment of various cancers and related inflammatory conditions. This review synthesizes the current understanding of gossypol as an anticancer agent, focusing on its pharmacological mechanisms, strategies to enhance its clinical efficacy, and the status of ongoing clinical evaluations.The methodological approach to this review involved a systematic search across several scientific databases including the National Center for Biotechnology Information (NCBI), PubMed/MedLine, Google Scholar, Scopus, and TRIP. Studies were meticulously chosen to cover various aspects of gossypol, from its chemical structure and natural sources to its pharmacokinetics and confirmed anticancer efficacy. Specific MeSH terms and keywords related to gossypol's antineoplastic applications guided the search strategy.Results from selected pharmacological studies indicate that gossypol inhibits the Bcl-2 family of anti-apoptotic proteins, promoting apoptosis in tumor cells. Clinical trials, particularly phase I and II, reveal gossypol's promise as an anticancer agent, demonstrating efficacy and manageable toxicity profiles. The review identifies the development of gossypol derivatives and novel carriers as avenues to enhance therapeutic outcomes and mitigate adverse effects.Conclusively, gossypol represents a promising anticancer agent with considerable therapeutic potential. However, further research is needed to refine gossypol-based therapies, explore combination treatments, and verify their effectiveness across cancer types. The ongoing clinical trials continue to support its potential, suggesting a future where gossypol could play a significant role in cancer treatment protocols.

RNA-binding proteins have increasingly been identified as important regulators of gene expression given their ability to bind distinct RNA sequences and regulate their fate. Mounting evidence suggests that RNA-binding proteins are involved in the onset and progression of multiple malignancies, prompting increasing interest in their potential for therapeutic intervention.The Musashi RNA binding proteins Musashi-1 and Musashi-2 were initially identified as developmental factors of the nervous system but have more recently been found to be ubiquitously expressed in physiological tissues and may be involved in pathological cell behavior. Both proteins are increasingly investigated in cancers given dysregulation in multiple tumor entities, including in female malignancies. Recent data suggest that the Musashi proteins serve as cancer stem cell markers as they contribute to cancer cell proliferation and therapy resistance, prompting efforts to identify mechanisms to target them. However, as the picture remains incomplete, continuous efforts to elucidate their role in different signaling pathways remain ongoing.In this review, we focus on the roles of Musashi proteins in tumors of the female - breast, endometrial, ovarian and cervical cancer - as we aim to summarize current knowledge and discuss future perspectives.

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Licoricidin (LCD) is an activity compound of the roots of Glycyrrhiza uralensis, which has therapeutic efficacy, including anti-virus, anti-cancer, and enhanced immunity in Traditional Chinese Medicine. Herein, this study aimed to clarify the effect of LCD on cervical cancer cells. In the present study, we found that LCD significantly inhibited cell viability via inducing cell apoptosis and companies with cleaved-PARP protein expression and caspase-3/-9 activity. Cell viability was markedly reversed these effects by pan-caspase inhibitor Z-VAD-FMK treatment. Furthermore, we showed that LCD-induced ER (endoplasmic reticulum) stress triggers upregulating the protein level of GRP78 (Bip), CHOP, and IRE1α, and subsequently confirmed the mRNA level by quantitative real-time polymerase chain reaction. In addition, LCD exhibited the release of danger-associated molecular patterns from cervical cancer cells, such as the release of high-mobility group box 1 (HMGB1), secretion of ATP, and exposure of calreticulin (CRT) on the cell surface, which led to immunogenic cell death (ICD). These results provide a novel foundation that LCD induces ICD via triggering ER stress in human cervical cancer cells. LCD might be an ICD inducer of immunotherapy in progressive cervical cancer.

Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition.