Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?

Cellular plasticity can occur naturally in an organism and is considered an adapting mechanism during the developmental stage. However, abnormal cellular plasticity is observed in different diseased conditions, including cancer. Cancer cell plasticity triggers the stimuli of epithelial-mesenchymal transition (EMT), abnormal epigenetic changes, expression of stem cell factors and implicated signaling pathways, etc., and helps in the maintenance of CSC phenotype. Conversely, CSC maintains the cancer cell plasticity, EMT, and epigenetic plasticity. EMT contributes to increased cell migration and greater diversity within tumors, while epigenetic changes, stem cell factors (OCT4, NANOG, and SOX2), and various signaling pathways allow cancer cells to maintain various phenotypes, giving rise to intra- and inter-tumoral heterogeneity. The intricate relationships between cancer cell plasticity and stem cell factors help the tumor cells adopt drug-tolerant states, evade senescence, and successfully acquire drug resistance with treatment dismissal. Inhibiting molecules/signaling pathways involved in promoting CSCs, cellular plasticity, EMT, and epigenetic plasticity might be helpful for successful cancer therapy management. This review discussed the role of cellular plasticity, EMT, and stem cell factors in tumor initiation, progression, reprogramming, and therapy resistance. Finally, we discussed how the intervention in this axis will help better manage cancers and improve patient survivability.

Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance.

Both genetic and epigenetic mechanisms intimately regulate cancer development and chemoresistance. Different genetic alterations are observed in multiple genes, and most are irreversible. Aside from genetic alterations, epigenetic alterations play a crucial role in cancer. The reversible nature of epigenetic modifications makes them an attractive target for cancer prevention and therapy. Specific epigenetic alteration is also being investigated as a potential biomarker in multiple cancers. c-MYC is one of the most important transcription factors that are centrally implicated in multiple types of cancer cells reprogramming, proliferation, and chemoresistance. c-MYC shows not only genetic alterations but epigenetic changes in multiple cancers. It has been observed that epigenome aberrations can reversibly alter the expression of c-MYC, both transcriptional and translational levels. Understanding the underlying mechanism of the epigenetic alterations of c-MYC, that has its role in multiple levels of cancer pathogenesis, can give a better understanding of various unresolved questions regarding cancer. Recently, some researchers reported that targeting the epigenetic modifiers of c-MYC can successfully inhibit cancer cell proliferation, sensitize the chemoresistant cells, and increase the patient survival rate. As c-MYC is an important transcription factor, epigenetic therapy might be one of the best alternatives for the conventional therapies that assumes the "one-size-fits-all" role. It can also increase the precision of targeting and enhance the effectiveness of treatments among various cancer subtypes. In this review, we highlighted the role of epigenetically modified c-MYC in cancer cell reprogramming, progression, and chemoresistance. We also summarize the potential therapeutic approaches to target these modifications for the prevention of cancer development and chemoresistant phenotypes.

Flubendiamide induced genetic and cellular damages directly influence the life cycle of the oriental leaf worm, Spodoptera litura.

Indiscriminate uses of insecticide greatly damage the environment as well as non-target organisms. Thus, multiple levels of bioassays can help better management of our environment. Flubendiamide is a phthalic acid diamide insecticide that ceases the function of insect muscle leading to paralysis and death. Here, we aimed to explore the effects of Flubendiamide on the life cycle of Spodoptera litura vis-a-vis the mode of action. Fourth instar larvae of the same age (120 ± 2 h) and size were fed with different concentrations (20-80 µg/mL) of Flubendiamide for 12-72 h. We performed a pharmacokinetics study, different biochemical assays, p450, Ecdysone receptor (EcR) and other genes expression analyses by Real-Time PCR and gross damages by Dye exclusion assay and histopathology. Our results demonstrate that the mean concentration of Flubendiamide after 48 h is 9.907 µg/mL and (i) altered the molting, metamorphosis, and reproduction at 80 µg/mL (24 h) (ii) increases all oxidative stress parameters (ROS/RNS, MDA, 8OHdG), decreases oxidative defense mechanisms (SOD, CAT, GST) at 80 µg/mL (48 h) and p450 in a time and concentration-dependent manner, (iii) activates CncC/Maf apoptotic pathways at 80 µg/mL concentration at 24 h while the expression declined from 48 h onwards, (iii) downregulates the EcR expression in a time and concentration-dependent manner, which might be responsible for disturbed molting, metamorphosis, and reproduction, and (iv) increase the expression of apoptotic genes (Caspase 1, -3, and - 5), in time and concentration-dependent manner causing gross morphological and histological damages. In conclusion, indiscriminate use of this insecticide can affect the ecosystem and have the capacity to cause multiple hazardous effects on experimental organisms. Thus, it warrants further investigations to improve and optimize the integrated pest management packages, including Flubendiamide for better management.

Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol.

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5-20 µM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10-50 µM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Role of long non-coding RNAs and MYC interaction in cancer metastasis: A possible target for therapeutic intervention.

The c-MYC is one of the most commonly discussed oncogenes in almost all cancers. c-MYC, as a proto-oncogene in normal cells, has found to be tightly controlled and regulated, both genetically and epigenetically. Evasion of the controlled checkpoint mechanisms during cancer causes a deregulated expression of c-MYC. Overexpression of c-MYC causes the onset of many hallmarks of cancer. Despite c-MYC being centrally located in several cancers, it is not feasible to target c-MYC in therapeutic resistant cancers. Similarly, long non-coding RNAs (lncRNAs) are deregulated during the genesis and progression of different cancers. LncRNAs contribute to almost 27% human genome and recent findings by tumor genome sequencing revealed many of the lncRNAs loci that are modified, deleted, amplified, and mutated during the different stages of cancer development. Recent studies also reported that multiple lncRNAs regulate c-MYC by different mechanisms and vice versa. Thus, oncogenic lncRNAs and c-MYC interaction are positioned to provide an interesting choice for therapeutic interventions in cancers. In this mini-review, we summarize the recent discoveries and explain how the interaction between oncogenic lncRNAs and c-MYC could be used as a possible target for therapeutic intervention in cancers, especially the therapeutic resistant metastatic cancers.

Chemotherapeutic potential of lupeol against cancer in pre-clinical model: A systematic review and meta-analysis.

BACKGROUND: Extensive research on Lupeol's potential in cancer prevention highlights its ability to target various cancer-related factors. It regulates proliferative markers, modulates signaling pathways, including PI3K/AKT/mTOR, and influences inflammatory and apoptotic mechanisms. Additionally, Lupeol demonstrates selectivity in killing cancer cells while sparing normal cells, thus minimizing the risk of toxic effects on healthy tissues. HYPOTHESIS: Therefore, we aimed to explore Lupeol's potential roles as a chemotherapeutic agent and as a sensitizer to chemotherapy by reviewing various animal-based studies published on its effects. STUDY DESIGN: We conducted a comprehensive search across databases, including PubMed, PMC, Cochrane, EuroPMC, and ctri.gov.in to identify pertinent articles. Our focus was solely on published animal studies examining Lupeol's anti-cancer effects, with reviewers independently assessing bias risk and resolving discrepancies through consensus. RESULT: 20 studies were shortlisted. The results demonstrated that Lupeol brings changes in the tumor volume by [Hedges's g: -6.62; 95 % CI: -8.68, -4.56; τ2: 24.36, I2: 96.50 %; p < 0.05] and tumor weight by [Hedges's g: -3.97; 95 % CI: -5.20, -2.49; τ2: 2.70, I2: 79.27 %; p <0.05]. The high I2, negative Egger's value, and asymmetrical funnel plot show the publication bias among the studies. Further, Lupeol in combination with other chemotherapeutic agents showed better outcomes as compared to them alone [Hedges's g: -6.38; 95 % CI: -11.82, -0.94; τ2: 46.91; I2: 98.68 %; p <0.05]. Lupeol also targets various signaling molecules and pathways to exert an anti-cancer effect. CONCLUSION: In conclusion, Lupeol significantly reduces tumor volume and weight. Combining Lupeol with other chemotherapy agents shows promise for enhancing anti-cancer effects. However, high variability among studies and evidence of publication bias suggest caution in interpreting results.

AURORA KINASE A and related downstream molecules: A potential network for cancer therapy.

Aurora-A kinase (AURKA) belongs to the serine/threonine kinase family specific to cell division. In normal cells, activation of the AURKA protein is essential for regulating chromosomal segregation and centrosome maturation. The physiological concentration of AURKA accumulation has utmost importance during cell division. AURKA starts accumulating during the S phase of the cell cycle, gets functionally activated during the G2/M phase, attaches to the microtubule, and gets degraded during mitotic exit. Overexpression of AURKA could lead to deregulated cell cycle division, which is intrinsic to numerous cancers. Moreover, dysregulated AURKA affects various downstream molecules that aid in cancer pathogenesis. AURKA phosphorylates its substrates, including oncoproteins, transcriptional factors, tumor suppressor proteins, or other kinases central to various oncogenic signaling pathways critical to cancer. Considering the central role of AURKA in cell proliferation and tumorigenesis, targeting AURKA can be a novel alternative to cancer management. Several AURKA inhibitors have shown promising responses against different cancers either as a single agent or combined with various therapies. This chapter briefly discusses the role of AURKA and its downstream molecules in cancer vis-à-vis the role of AURKA inhibitor in chemoprevention.

Research and Patents Status of Selected Phytochemicals Against Cancer: How Close and How Far?

BACKGROUND: Cancer is a global health issue and economic burden with a continuous increase in incidence and mortality. Over the years, the underlying molecular mechanism of cancers was thoroughly researched, leading to multiple drugs' development. Unfortunately, most drugs have some serious drawbacks, such as therapy resistance and toxicity. Epidemiological studies have shown that a diet rich in fruits and vegetables has cancer prevention properties, which shifted the attention to the potential role of phytochemicals in anti-carcinogenic activity. OBJECTIVE: To review the present status of phytochemicals research and patents in cancer prevention and chemosensitization. METHODS: We explored the relevant published articles and patents to review the phytochemicals showing cancer preventive role in preclinical settings from 1997 onwards. RESULTS: We summarise the role of phytochemicals on anti-carcinogenic, anti-inflammatory, antiproliferative, anti-metastatic, and pro-apoptotic activities in both in vitro and in vivo. Thus, phytochemicals might be an excellent chemosensitizing agent against chemoresistant cells and possibly one of the safest and most effective options for cancer therapy. However, one of the limitations of phytochemicals is their poor bioavailability and rapid excretion. Several analogs have been introduced to increase bioavailability, better biological efficacy, absorption, and retention. In fact, various phytochemicals and their analogs have been patented for their anti-cancerous properties. CONCLUSION: This mini-review discusses various phytochemicals and their anti-cancerous and chemosensitizing roles. Due to their clinical relevance, recent trends in phytochemical extraction and exploration have shown that more and more phytochemicals are being patented.

Implication of Lupeol in compensating Sorafenib-induced perturbations of redox homeostasis: A preclinical study in mouse model.

AIMS: Cancer chemotherapeutic drugs can potentially cause several adverse effects that influence a patient's general well-being. Sorafenib, an approved drug used in clinics against multiple cancers whose overall efficacy suffered a serious setback due to various side effects, leading to its frequent discontinuation. Lupeol has recently been considered an important prospective therapeutic agent due to its low toxicity and enhanced biological efficacy. Hence, our study aimed to evaluate whether Lupeol can perturb the Sorafenib-induced toxicity. MAIN METHODS: To test our hypothesis, we studied DNA interaction, level of cytokines, LFT/RFT, oxidant/antioxidant status, and their influences on genetic, cellular, and histopathological changes using both in vitro and in vivo models. KEY FINDINGS: The Sorafenib-treated group showed a marked increase in reactive oxygen and nitrogen species (ROS/RNS), an increase in liver and renal function marker enzymes, serum cytokines (IL-6, TNF-α, IL-1ß) macromolecular damages (protein, lipid, and DNA), and a decrease in antioxidant enzymes (SOD, CAT, TrxR, GPx, GST). Moreover, Sorafenib-induced oxidative stress caused marked cytoarchitectural damage in the liver and kidney and increased p53 and BAX expression. Interestingly, combining Lupeol with Sorafenib improves all the examined toxic insults caused by Sorafenib. In conclusion, our findings suggest that Lupeol can be used in combination with Sorafenib to reduce ROS/RNS-induced macromolecule damage, which might result in hepato-renal toxicity. SIGNIFICANCE: This study presents the possible protective effect of Lupeol against Sorafenib-induced adverse effects by perturbing redox homeostasis imbalance and apoptosis leading to tissue damage. This study is a fascinating finding that warrants further in-depth preclinical and clinical studies.

Molecular Insight into Prostate Cancer: Preventive Role of Selective Bioactive Molecules.

Prostate cancer (CaP) is one of the most prevalent male malignancies, accounting for a considerable number of annual mortalities. However, the prompt identification of early-stage CaP often faces delays due to diverse factors, including socioeconomic inequalities. The androgen receptor (AR), in conjunction with various other signaling pathways, exerts a central influence on the genesis, progression, and metastasis of CaP, with androgen deprivation therapy (ADT) serving as the primary therapeutic strategy. Therapeutic modalities encompassing surgery, chemotherapy, hormonal intervention, and radiotherapy have been formulated for addressing early and metastatic CaP. Nonetheless, the heterogeneous tumor microenvironment frequently triggers the activation of signaling pathways, culminating in the emergence of chemoresistance, an aspect to which cancer stem cells (CSCs) notably contribute. Phytochemicals emerge as reservoirs of bioactive agents conferring manifold advantages against human morbidity. Several of these phytochemicals demonstrate potential chemoprotective and chemosensitizing properties against CaP, with selectivity exhibited towards malignant cells while sparing their normal counterparts. In this context, the present review aims to elucidate the intricate molecular underpinnings associated with metastatic CaP development and the acquisition of chemoresistance. Moreover, the contributions of phytochemicals to ameliorating CaP initiation, progression, and chemoresistance are also discussed.

Role of lupeol in chemosensitizing therapy-resistant prostate cancer cells by targeting MYC, ß-catenin and c-FLIP: in silico and in vitro studies.

Prostate cancer (CaP) is one of the most frequent malignancies amongst men. Enzalutamide is the second-generation potent androgen receptor (AR) antagonist used against metastatic and non-metastatic CaP. Unfortunately, the development of chemoresistance in cancer cells reduces the effectiveness of Enzalutamide. Lupeol is a pentacyclic triterpene found in different fruits, vegetables, and medicinal plants and possesses anti-inflammatory and anti-cancer properties. Here, we report in silico and in vitro studies of Lupeol and Enzalutamide against the ß-CATENIN, c-FLIPL, and c-MYC, which play a significant role in chemoresistance. We observed that Lupeol significantly inhibits the cell growth of chemoresistant Du145 cells and cancer stem cells (CSCs) either alone or in combination with Enzalutamide. Lupeol and Enzalutamide were also found to dock with ß-CATENIN, c-FLIPL, and c-MYC. The following MD simulation data showed both compounds exerting structural changes in these proteins. Finally, they significantly inhibit the transcriptional activity of all these genes, as observed by luciferase assay. Thus, we infer that Lupeol chemosensitizes the CaP cells for Enzalutamide-resistant CaP cells.

Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer.

Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel-like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.Area covered: We cover recent discoveries and investigate the role of OSKM in inducing pluripotency and stem cell-like properties in various cancers with special emphasis on liver cancer. We review Yamanaka factors' role in stemness and chemoresistance of liver cancer.Expert opinion: In CSCs, including liver CSCs, the deregulation of various signaling pathways is one of the major reasons for stemness and drug resistance and is primarily due to OSKM. OSKM are responsible for tumor heterogeneity which renders targeting drug useless after a certain period. These factors can be exploited to understand the underlying mechanism of cancer stemness and resistance to chemotherapeutic drugs.

The multiple faces of NANOG in cancer: a therapeutic target to chemosensitize therapy-resistant cancers.

The transcription factor NANOG regulates self-renewal and pluripotency in embryonic cells, and its downregulation leads to cell differentiation. Recent studies have linked upregulation of NANOG in various cancers and the regulation of expression of different molecules, and vice versa, to induce proliferation, metastasis, invasion and chemoresistance. Thus NANOG is an oncogene that functions by inducing stem cells' circuitries and heterogeneity in cancers. Understanding NANOG's role in various cancers may lead to it becoming a therapeutic target to halt cancer progression. The NANOG network can also be targeted to resensitize resistant cancer cells to conventional therapies. The current review focuses on NANOG regulation in the various signaling networks leading to cancer progression and chemoresistance, and highlights the therapeutic aspect of targeting NANOG in various cancers.

Lay abstract NANOG is a gene that is mainly expressed during development of the embryo. In adult tissues, NANOG is hardly expressed. In embryonal cells, NANOG is responsible for generating stem cells. Once the cells are differentiated into their specific function, they no longer need this renewing property. So expression of NANOG in differentiated 'adult' cells is harmful as it helps tumor cells to grow. NANOG expression also enables the tumor cells to keep on evolving their microenvironment, thus making it difficult for conventional therapy to destroy them. This review highlights the factors that influence NANOG's expression in cancer progression and chemoresistance and how it can be targeted for therapy.