NPJ Precis Oncol. Feb 2024

Malignant pleural mesothelioma (MPM) is a rare but lethal pleural cancer with high intratumor heterogeneity (ITH). A recent study in lung adenocarcinoma has developed a clonal gene signature (ORACLE) from multiregional transcriptomic data and demonstrated high prognostic values and reproducibility. However, such a strategy has not been tested in other types of cancer with high ITH. We aimed to identify biomarkers from multi-regional data to prognostically stratify MPM patients. We generated a multiregional RNA-seq dataset for 78 tumor samples obtained from 26 MPM patients, each with one sample collected from a superior, lateral, and inferior region of the tumor. By integrating this dataset with the Cancer Genome Atlas MPM RNA-seq data, we selected 29 prognostic genes displaying high variability across different tumors but low ITH, which named PRACME (Prognostic Risk Associated Clonal Mesothelioma Expression). We evaluated PRACME in two independent MPM datasets and demonstrated its prognostic values. Patients with high signature scores are associated with poor prognosis after adjusting established clinical factors. Interestingly, the PRACME and the ORACLE signatures defined respectively from MPM and lung adenocarcinoma cross-predict prognosis between the two cancer types. Further investigation indicated that the cross-prediction ability might be explained by the high similarity between the two cancer types in their genomic regions with copy number variation, which host many clonal genes. Overall, our clonal signature PRACME provided prognostic stratification in MPM and this study emphasized the importance of multi-regional transcriptomic data for prognostic stratification based on clonal genes.

Nat Genet. Mar 2023. doi: 10.1038/s41588-023-01321-1

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Cells. Oct 2022

Despite therapeutic advancements, lung cancer remains the principal cause of cancer mortality in a global scenario. The increased incidence of tumor reoccurrence and progression and the highly metastatic nature of lung cancer are of great concern and hence require the investigation of novel therapies and/or medications. Naturally occurring compounds from plants serve as important resources for novel drugs for cancer therapy. Amongst these phytochemicals, Berberine, an alkaloid, has been extensively explored as a potential natural anticancer therapeutic agent. Several studies have shown the effectiveness of Berberine in inhibiting cancer growth and progression mediated via several different mechanisms, which include cell cycle arrest, inducing cell death by apoptosis and autophagy, inhibiting cell proliferation and invasion, as well as regulating the expression of microRNA, telomerase activity, and the tumor microenvironment, which usually varies for different cancer types. In this review, we aim to provide a better understanding of molecular insights of Berberine and its various derivative-induced antiproliferative and antimetastatic effects against lung cancer. In conclusion, the Berberine imparts its anticancer efficacy against lung cancers via modulation of several signaling pathways involved in cancer cell viability and proliferation, as well as migration, invasion, and metastasis.

Front Pharmacol. 2021. doi: 10.3389/fphar.2021.775514

Background: Berberine is one of the most interesting and promising natural anticancer drugs. POLE2 is involved in many cellular functions such as DNA replication and is highly expressed in a variety of cancers. However, the specific molecular mechanism of berberine interfering with POLE2 expression in lung adenocarcinoma (LUAD) is still unknown to a great extent. Method: The KEGG database (Release 91.0) and Gene Ontology (GO) category database were used for functional annotation of differentially expressed genes after berberine treatment. Reproducibility assessment using TCGA dataset. The biological functions of berberine in LUAD were investigated by a series of in vitro and in vivo experiments: MTT, colony formation, mouse xenograft and plasmid transfection. The molecular mechanisms of berberine were demonstrated by plasmid transfection, quantitative RT-PCR and Western blotting. Result: The elevated expression of FOXM1 and the high enrichment of DNA replication pathway were confirmed in LUAD by microarray and TCGA analysis, and were positively correlated with poor prognosis. Functionally, berberine inhibited the proliferation and survival of LUAD cell lines in vitro and in vivo. Mechanistically, berberine treatment down regulated the expression of FOXM1which closely related to survival, survival related genes in Cell cycle and DNA replication pathway, and significantly down regulated the expression of survival related POLE2. Interestingly, we found that the transcription factor FOXM1 could act as a bridge between berberine and POLE2. Conclusion: Berberine significantly inhibited LUAD progression via the FOXM1/POLE2, and FOXM1/POLE2 may act as a clinical prognostic factor and a therapeutic target for LUAD. Berberine may be used as a promising therapeutic candidate for LUAD patients.

Adv Biol Regul. Jan 2022

Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). A key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, cancer progression and other growth regulatory processes. The mouse double minute 2 homolog (MDM2) gene product is a nuclear-localized E3 ubiquitin ligase and negatively regulates the TP53 protein which results in its proteasomal degradation. Various MDM2 inhibitors have been isolated and examined in clinical trials, especially in patients with hematological malignancies. Nutlin-3a is one of the first MDM2 inhibitors isolated. Berberine (BBR) is a natural product found in many fruits and berries and used in traditional medicine for centuries. It has many biological effects, and some are anti-proliferative in nature. BBR may activate the expression of TP53 and inhibit cell cycle progression as well as other events important in cell growth. To understand more about the potential of compounds like BBR and chemical modified BBRs (NAX compounds) to sensitize PDAC cells to MDM2 inhibitors, we introduced either WT-TP53 or the pLXSN empty vector control into two PDAC cell lines, one lacking expression of TP53 (PANC-28) and one with gain-of-function mutant TP53 on both alleles (MIA-PaCa-2). Our results indicate that nutlin-3a was able to increase the sensitivity to BBR and certain NAX compounds. The effects of nutlin-3a were usually more substantial in those cells containing an introduced WT TP53 gene. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function by stabilization of the TP53 protein.

Biomolecules. Feb 2022

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. In ~75% of PDAC, the tumor suppressor TP53 gene is mutated. Novel approaches to treat cancer involve compounds called mutant TP53 reactivators. They interact with mutant TP53 proteins and restore some of their growth suppressive properties, but they may also interact with other proteins, e.g., TP63 and TP73. We examined the ability of the TP53 reactivator APR-246 to interact with eleven modified berberine compounds (NAX compounds) in the presence and absence of WT-TP53 in two PDAC cell lines: the MIA-PaCa-2, which has gain of function (GOF) TP53 mutations on both alleles, and PANC-28, which lacks expression of the WT TP53 protein. Our results indicate the TP53 reactivator-induced increase in therapeutic potential of many modified berberines.

Bioorg Med Chem. 05 2021

In the last few decades, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding perpetually. Berberine, with remarkable therapeutic diversity, is a plant derived isoquinoline alkaloid which is widely used as a traditional medicine in China. Berberine has been tackled as a fascinating pharmacophore to make great contributions to the discovery and development of new therapeutic agents against variegated diseases. Despite its tremendous therapeutic potential, clinical utility of this alkaloid was significantly compromised due to undesirable pharmacokinetic properties. To overcome this limitation, several structural modifications were performed on this scaffold to improve its therapeutic efficacy. The collective efforts of the community have achieved the tremendous advancements, bringing berberine to clinical use and discovering new therapeutic opportunities by structural modifications on the berberine scaffold. In this review, recent advancements in the medicinal chemistry of berberine and its derivatives in the last few years (2016-2020) have been compiled to represent inclusive data associated with various biological activities of this alkaloid. The comprehensive structure-activity relationship studies along with molecular modelling and mechanistic studies have also been summarized. This article would be highly helpful for the scientific community to get better insight into medicinal research of berberine and become a compelling guide for the rational design of berberine based compounds.

Int J Mol Sci. May 2020

Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the protein quality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs.We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action.We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein.BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders.

Acta Biomater. Sep 2019

Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-deliveries doxorubicin (DOX) and BER to achieve a synergic effect in HCC treatment. The underlying fact of chemotherapy that promotes HCC repopulation was firstly examined and corroborated by clinical samples and murine repopulation model. Then, hyaluronic acid (HA)-conjugated Janus nanocarrier (HA-MSN@DB) was developed to load DOX and BER simultaneously. The HCC targeting efficiency, pH-controlled drug-release and anti-cancer property of HA-MSN@DB were assessed in CD44-overexpressed HCCs and normal liver cells. Magnet resonance imaging, bio-distribution, biocompatibility, tumor and recurrence inhibition studies were performed in H22 tumor-bearing mice. BER significantly reduced doxorubicin (DOX)-triggered HCC repopulation in vitro and in vivo through inhibiting Caspase-3-iPLA2-COX-2 pathway. The delivery of HA-MSN@DB into HCCs through CD44 receptor-mediated targeting effect was demonstrated. The controlled release of DOX and BER in response to acidic tumor microenvironment was validated. Importantly, HA-MSN@DB drastically enhanced the antitumor activity of DOX and suppressed DOX-exacerbated HCC repopulation in vitro and in vivo. Furthermore, HA-MSN@DB exhibited enhanced tumor accumulation and biocompatibility. Our findings revealed the pivotal role of BER in overcoming chemotherapy-exacerbated HCC repopulation through Caspase-3-iPLA2-COX-2 pathway, thereby providing a promising and stable nanocarrier integrating DOX and BER for effective HCC chemotherapy without repopulation. Statement of Significance In this work, we have first demonstrated the fact that berberine (Ber) reduces chemotherapy-exacerbated HCC recurrence and studied its mechanism by the aid of a doxorubicin-induced mice HCC relapse model. We then developed a promising strategy that simultaneously inhibits HCC and its recurrence with an HCC-targeted co-delivery nanocarrier HA-MSN@DB and revealed that such an inhibition was related with the suppression of Caspase-3-iPLA2-COX-2 pathway by berberine.

Adv Biol Regul. Jan 2019

Berberine (BBR) is a common nutraceutical consumed by millions worldwide. BBR has many different effects on human health, e.g., diabetes, diarrhea, inflammation and now more recently it has been proposed to have potent anti-cancer effects. BBR has been shown to suppress the growth of cancer cells more than normal cells. BBR has been proposed to exert its growth-inhibitory effects by many different biochemical mechanisms including: suppression of cell cycle progression, induction of reactive oxygen species, induction of apoptosis and autophagy and interactions with DNA potentially leading to DNA damage, and altered gene expression. Pancreatic cancer is a leading cancer worldwide associated with a poor prognosis. As our population ages, pancreatic cancer has an increasing incidence and will likely become the second leading cause of death from cancer. There are few truly-effective therapeutic options for pancreatic cancer. Surgery and certain chemotherapeutic drugs are used to treat pancreatic cancer patients. Novel approaches to treat pancreatic cancer patients are direly needed as they usually survive for less than a year after being diagnosed. In the following manuscript, we discuss the abilities of BBR and certain chemically-modified BBRs (NAX compounds) to suppress growth of pancreatic cancer cells.

Adv Biol Regul. Aug 2019

Pancreatic cancer is devastating cancer worldwide with few if any truly effective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more effective therapeutic approaches are needed as pancreatic cancer patients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as diabetes mellitus has been examined in association with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may affect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the effects of metformin. One "medicinal" fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism. Glucose metabolism has been shown to be very important in cancer and its significance is increasing. In the following studies, we have examined the effects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four different human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the effects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by combining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells.

Int J Biol Macromol. 2015

Topoisomerases IB are anticancer and antimicrobial targets whose inhibition by several natural and non-natural compounds has been documented. The inhibition effect by berberine and some 13-(di)phenylalkyl berberine derivatives has been tested towards human topoisomerase IB. Derivatives belonging to the 13-diphenylalkyl series display an efficient inhibition of the DNA relaxation and cleavage step, that increases upon pre-incubation with the enzyme. The religation step of the enzyme catalytic cycle is not affected by compounds and only slightly upon pre-incubation. The binding of the protein to the DNA substrate occurs also in the presence of the compounds, as monitored by a DNA shift assay, indicating that the compounds are not able to inhibit the formation of the enzyme-DNA complex but that they act as catalytic inhibitors.

doi: 10.1016/j.ijbiomac.2015.02.051S0141-8130(15)00155-5

Biomed Res Int. 2014

The pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inflammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their effects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more affected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives.

doi: 10.1155/2014/924585

Biofactors 2013

Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 µM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 µM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines.

doi: 10.1002/biof.1131

Biofactors 2013

Aberrant activation of the canonical Wnt/β-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in β-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/β-catenin signaling is of specific therapeutic interest. Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects on Wnt/β-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 µM. Berberine inhibited β-catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active β-catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on β-catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior to those of the naturally occurring parent substance with more than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/β-catenin signaling in tumorigenesis.

doi: 10.1002/biof.1133

Biochem Pharmacol. 2012

Chemical compounds derived from plants have been used since the origin of human beings to counteract a number of diseases. Among them, the natural isoquinoline alkaloid berberine has been employed in Ayurvedic and Chinese Medicine for hundreds of years with a wide range of pharmacological and biochemical effects. More recently, a growing body of reports supports the evidence that berberine has anticancer effects, being able to block the proliferation of and to kill cancer cells. This review addresses the properties and therapeutic use of berberine and focuses on the recent advances as promising anticancer drug lead.

doi: 10.1016/j.bcp.2012.07.018S0006-2952(12)00500-X

Adv Biol Regul. Jan 2018

Over the past fifty years, society has become aware of the importance of a healthy diet in terms of human fitness and longevity. More recently, the concept of the beneficial effects of certain components of our diet and other compounds, that are consumed often by different cultures in various parts of the world, has become apparent. These "healthy" components of our diet are often referred to as nutraceuticals and they can prevent/suppress: aging, bacterial, fungal and viral infections, diabetes, inflammation, metabolic disorders and cardiovascular diseases and have other health-enhancing effects. Moreover, they are now often being investigated because of their anti-cancer properties/potentials. Understanding the effects of various natural products on cancer cells may enhance their usage as anti-proliferative agents which may be beneficial for many health problems. In this manuscript, we discuss and demonstrate how certain nutraceuticals may enhance other anti-cancer drugs to suppress proliferation of cancer cells.

DOI: 10.1016/j.jbior.2017.09.012