Efficacy Of Chemotherapeutic Drugs Research Articles

The phytochemical plumbagin: mechanism behind its "pleiotropic" nature and potential as an anticancer treatment.

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations.

RETRACTION: Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress.

RETRACTION: Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress.

Influence of Nanomedicine as a Smart Weapon on Multidrug Resistance in Cancer Therapy.

Cancer is the leading cause of death worldwide. The effectiveness of chemotherapy in cancer patients is still significantly hampered by Multidrug Resistance (MDR). Tumors exploit the MDR pathways to invade the host and limit the efficacy of chemotherapeutic drugs that are delivered as single drugs or combinations. Further, overexpression of ATP-binding Cassette transporter (ABC transporter) proteins augments the efflux of chemotherapeutic drugs and lowers their intracellular accumulation. Recent progress in the development of nanotechnology and nanocarrier-based drug delivery systems has shown a better perspective with respect to the improvement of cancer chemotherapy. Nanoparticles/nanomaterials are designed to target the immune system and tumor microenvironment of cancer cells for a variety of cancer treatments in order to improve bioavailability and reduce toxicity. This review elucidates the successful use of nanomaterials for cancer therapy and addressing the MDR and throws some light on the present obstacles impeding their translation to clinical use.

Advancements in Pancreatic Cancer Treatment: A Comprehensive Review of Current Therapies and Future Directions

Pancreatic cancer still has a 5-year survival rate in the single digits, making it one of the most aggressive and deadly cancers. The therapy of pancreatic cancer presents considerable hurdles because of its late diagnosis, fast development, and resistance to traditional therapies, even with advancements in oncological research. This study offers a thorough summary of the various treatment options available today, including as radiation therapy, chemotherapy, surgery, and the newly recognized roles of immunotherapy and targeted medicines. We examine the most recent advancements in personalized medicine and molecular profiling, which are starting to challenge established therapy paradigms and provide fresh hope for bettering patient outcomes. The study also outlines ongoing clinical trials that attempt to address the shortcomings of current therapy, such as the toxicity and limited efficacy of chemotherapeutic drugs. This study aims to provide a comprehensive overview of the pancreatic cancer therapy landscape by analyzing both conventional and cutting-edge treatments. It also identifies promising directions for future research and clinical practice.

Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics

A high abundance of Epidermal Growth Factor Receptor (EGFR) in malignant cells makes them a prospective therapeutic target for basal breast tumors. Although EGFR inhibitors are in development as anticancer therapeutics, there exists limitations due to the dose-limiting cytotoxicity that limits their clinical utilization, thereby necessitating the advancement of effective inhibitors. In the present study, we have developed common pharmacophore hypotheses using 30 known EGFR inhibitors. The best pharmacophore hypothesis DHRRR_1 was utilized for virtual screening (VS) of the Phase database containing 4.3 × 106 fully prepared compounds. The top 1000 hits were further subjected to ADME filtration followed by structure-based VS and Molecular Dynamics (MD) simulation investigations. Based on pharmacophore hypothesis matching, XP glide score, interactions between ligands and active site residues, ADME properties, and MD simulations, the five best hits (SN-01 through SN-05) were preferred for in-vitro cytotoxicity studies. All the molecules except SN-02 exhibited cytotoxicity in Triple Negative Breast Cancer (TNBC) cells. These potential EGFR inhibitors effectively downregulated the EGF-induced proliferation, migration, in-vitro tumorigenic capability, and EGFR activation (pEGFR) in the TNBCs. Additionally, in combination with doxorubicin, the identified EGFR inhibitors significantly decreased the EGF-induced proliferation. SN-04, and SN-05 in the presence of a lower concentration of doxorubicin markedly increased the apoptotic markers expression in the TNBCs, an effect which was comparable to a higher concentration of doxorubicin treatment, alone. These observations suggest that both SN-04 and/or SN-05 can improve the efficacy of chemotherapeutic drug, doxorubicin at a lower concentration to avert the higher dose of chemotherapeutic-induced side effects during breast cancer treatment.

Microchip Based Isolation and Drug Delivery of Patient-Derived Extracellular Vesicles Against Their Homologous Tumor.

Extracellular vesicles (EVs) have demonstrated significant potential in drug delivery and anti-tumor therapy. Despite this promising strategy, challenges such as specific targeting, EVs purification persist. In this study, a personalized nanodrug delivery platform using patient-derived tumor EVs (PT-EVs) based on a microchip is presented. The microchip integrates multiple functions, including capture, enrichment, drug loading, and elution of PT-EVs. The isolation and drug-carrying procedures are completed within a 12 h timeframe, achieving a recovery rate of 65%, significantly surpassing the conventional ultracentrifuge (UC) method. Furthermore, PT-EVs derived from patient tumor models are first utilized as natural drug carriers, capitalizing on their inherent homing ability to precisely target homologous tumors. Lenvatinib and doxorubicin (DOX), two commonly utilized drugs in the clinical treatment of hepatocellular carcinoma (HCC), are loaded into PT-EVs and delivered to a matched in vitro tumor model that recapitulates original tumors for drug susceptibility testing. As is proven, PT-EVs exhibit robust tumor cell targeting and efficient receptor-mediated cellular uptake, and the efficacy of chemotherapeutic drugs is improved significantly. These results suggest that this platform could be a valuable tool for efficient isolation of PT-EVs and personalized drug customization, particularly when working with limited clinical samples, thus supporting personalized and precision medicine.

Aqueous Extracts of Ocimum gratissimum Sensitize Hepatocellular Carcinoma Cells to Cisplatin through BRCA1 Inhibition.

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.

Aversatile MOF as an electrochemical/fluorescence/colorimetric signal probe for the tri-modal detection of MMP-9 secretion in the extracellular matrix to identify the efficacy of chemotherapeutic drugs

BackgroundMMP-9 plays a crucial role in regulating the degradation of proteins within the extracellular matrix (ECM). This process closely correlates with the occurrence, development, invasion, and metastasis of various tumors, each exhibiting diverse levels of MMP-9 expression. However, the accuracy of detection results using the single-mode method is compromised due to the coexistence of multiple biologically active substances in the ECM. ResultsTherefore, in this study, a tri-modal detection system is proposed to obtain more accurate information by cross-verifying the results. Herein, we developed a tri-modal assay using the ZIF-8@Au NPs@S QDs composite as a multifunctional signal probe, decorated with DNA for the specific capture of MMP9. Notably, the probe demonstrated high conductivity, fluorescence response and mimicked enzyme catalytic activity. The capture segments of hybrid DNA specifically bind to MMP9 in the presence of MMP9, causing the signal probe to effortlessly detach the sensor interface onto the sample solution. Consequently, the sensor current performance is weakened, with the colorimetric and fluorescent signals becoming stronger with increasing MMP9 concentration. Notably, the detection range of the tri-modal sensor platform spans over 10 orders of magnitude, verifying notable observations of MMP-9 secretion in four tumor cell lines with chemotherapeutic drugs. Furthermore, the reliability of the detection results can be enhanced by employing pairwise comparative analysis. SignificanceThis paper presents an effective strategy for detecting MMP9, which can be utilized for both the assessment of MMP-9 in cell lines and for analyzing the activity and mechanisms involved in various tumors.

Lentinan Regulates Glioma Cell Proliferation and Apoptosis by Activating p53 and Caspases Pathways

Background Gliomas are highly lethal malignancies that develop in the central nervous system. The primary treatment for gliomas involves surgical resection followed by chemoradiotherapy. However, due to the infiltrative growth nature of gliomas, surgical resection is often incomplete. Moreover, the efficacy of chemotherapeutic drugs is constrained by their ability to cross the blood–brain barrier, and the currently utilized agents can lose effectiveness, particularly with prolonged administration. Lentinan, an active compound in Lentinula edodes, exhibits various pharmacological activities. Purpose This study aims to investigate the anti-tumor effects of lentinan on glioma U251 cells. Methods Cell proliferation assays, cell fluorescence staining, scratch healing experiments, and transwell chamber experiments were conducted to assess the anti-tumor activity of lentinan on U251 cells. Additionally, quantitative real-time polymerase chain reaction (qPCR) and Western blot experiments were performed to validate the anti-tumor mechanism of lentinan. Results The findings revealed that lentinan significantly suppressed the proliferation of U251 cells, induced robust apoptosis, and decreased the cells’ migration and invasion capabilities. Furthermore, lentinan notably influenced the gene and protein expression of P53, Bcl-2, Cyto-c, Bax, Caspases, and MMP-9 in U251 cells. Conclusion These findings suggest that lentinan may inhibit glioma cells by activating P53 and caspase-related apoptosis pathways.

PH-responsive drug-loaded peptides enhance drug accumulation and promote apoptosis in tumor cells

The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising.

Protease-activated receptor 2: a promising therapeutic target for women's cancers.

Cancers affecting women, such as breast, uterine, ovarian, endometrial and cervical cancers, have become increasingly prevalent. The growing incidence and death rates associated with these cancers warrant the development of innovative and alternative approaches to current treatments. This article investigates the association of women's cancers with a molecular target known as protease-activated receptor 2 (PAR2), a G-protein coupled receptor that is expressed on the surface of cancer cells. Expression levels of the PAR2 gene were curated from publicly available databases and were found to be significantly overexpressed in tissues from patients with breast, uterine, ovarian, endometrial or cervical cancer compared to normal tissues. PAR2 overexpression has been previously linked to tumor progression and, in some cases, tumor growth. Activation of PAR2 by either endogenous proteases or synthetic agonists triggers certain downstream intracellular signaling pathways that have been associated with tumor progression, cell migration and invasion, angiogenesis and apoptosis of cancer cells. While recent advances have led to the identification of several PAR2 antagonists, none has yet been developed for human use. Additionally, PAR2 inhibition has been shown also to increase the efficacy of chemotherapeutic drugs, allowing them to be potentially used at less toxic doses in combination therapies for cancer. The present work briefly summarizes the current status of PAR2 as a potential therapeutic target for treating women's cancers. Significance Statement This article highlights potential roles for PAR2 in cancers affecting women. Overexpression of the PAR2 gene in women's cancers is associated with various oncogenic processes such as tumor progression, cell migration and invasion, ultimately contributing to poorer patient prognoses. Given the increasing incidence of women's cancers, there is an urgent need to develop novel therapeutic drugs and PAR2 represents a promising target for developing new treatments.

PLGA-based nanocarriers for combined delivery of colchicine and purpurin 18 in cancer therapy: Multimodal approach employing cancer cell spheroids

Improving the anticancer efficacy of chemotherapeutic drugs and photosensitizers requires innovative multifunctional nanoplatforms. This study introduces a chemo- and phototherapeutic drug delivery system (DDS) based on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), both PEGylated and non-PEGylated, with a mean size of 200 ± 75 nm. Colchicine (Colch) and purpurin18 (P18) were co-encapsulated into these NPs, and their in vitro drug release profiles were investigated. The anticancer potential of these systems was evaluated across various cell lines (i.e., CaCo-2, PC-3, MCF-7, and MRC-5 cells), demonstrating enhanced NP uptake by cancer cells compared to free drugs. Co-administration of Colch and P18 in 2D and 3D cell line models exhibited a synergistic effect, harnessing both chemotherapeutic and photodynamic effects, leading to higher cancer cell elimination efficacy. This newly developed multifunctional DDS presents a promising platform for combined chemo- and photodynamic therapy in cancer treatment.

Berberine-based self-assembly agents with enhanced synergistic antitumor efficacy.

Tumors are still a major threat to people worldwide. Nanodrug delivery and targeting systems can significantly improve the therapeutic efficacy of chemotherapeutic drugs for antitumor purposes. However, many nanocarriers are likely to exhibit drawbacks such as a complex preparation process, limited drug-loading capacity, untargeted drug release, and toxicity associated with nanocarriers. Therefore, new therapeutic alternatives are urgently needed to develop antitumor drugs. Natural products with abundant scaffold diversity and structural complexity, which are derived from medicinal plants, are important sources of new antitumor drugs. Here, two carrier-free berberine (BBR)-based nanoparticles (NPs) were established to increase the synergistic efficacy of tumor treatment. BBR can interact with glycyrrhetinic acid (GA) and artesunate (ART) to self-assemble BBR-GA and BBR-ART NPs without any nanocarriers, respectively, the formation of which is dominated by electrostatic and hydrophobic interactions. Moreover, BBR-GA NPs could lead to mitochondria-mediated cell apoptosis by regulating mitochondrial fission and dysfunction, while BBR-ART NPs induced ferroptosis in tumor cells. BBR-based NPs have been demonstrated to possess significant tumor targeting and enhanced antitumor properties compared with those of simple monomer mixes both in vitro and in vivo. These carrier-free self-assemblies based on natural products provide a strategy for synergistic drug delivery and thus offer broad prospects for developing enhanced antitumor drugs.

Abstract B055: Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance

Abstract Metabolic heterogeneity in breast cancer has limited the deployment of metabolic therapies. To enable patient stratification, we studied global metabolic landscape of breast cancer (N>3000 combined) and identified three metabolic subtypes with increasing degrees of metabolic deregulation. M1 exhibited deregulated bile acid biosynthesis whereas M2 showed reliance on methionine pathway and M3 was found to be the most metabolically aggressive engaging fatty, nucleotide, and glucose metabolism. Extent of metabolic deregulation correlated strongly with tumor aggressiveness and patient outcome Moreover bile acid biosynthesis predicted less aggressive tumors with better prognosis while pyrimidine metabolism predicted the opposite trend. Notably this pattern was reproducible in independent datasets and in vivo tumor metabolite data. Genomic characterization of metabolic subtypes revealed TP53 mutation and MYC amplification as the strongest predictor of metabolic deregulation. Using machine learning, we identified robust and generalizable signatures that recaptured metabolic subtypes in tumors and cell lines. Surprisingly, the least deregulated M1 subtype was not found to be represented by any of the 50 cell line models analyzed. Experimental inhibition of metabolic pathways demonstrated subtype specific sensitivity and improved combinatorial efficacy of chemotherapeutic drugs. In addition, breast cancer cell lines representing metabolic subtypes revealed therapeutically relevant drugs. Taken together, this work presents metabolic stratification of breast cancer patients that may have implications in predicting patient outcome and designing precision therapies. Citation Format: Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B055.

Brusatol increases chemotherapeutic drug efficacy in pancreatic ductal adenocarcinoma by suppressing Nrf2 signaling

Chemoresistance to gemcitabine (Gem) remains a substantial obstacle in the treatment of pancreatic ductal adenocarcinoma carcinoma (PDAC). Nrf2, a transcription factor responsive to oxidative stress, has been implicated as a key contributor to chemoresistance. Previous studies have demonstrated anti-tumor effects of brusatol (BRT) in PDAC. Herein, we aimed to investigate the efficacy of BRT in enhancing chemosensitivity to Gem and to elucidate the underlying mechanisms involving Nrf2. Gain- and-loss-of-function experiments revealed that Nrf2 exacerbated Gem chemoresistance in PDAC cells. Additionally, BRT effectively inhibited PDAC cell proliferation and enhanced Gem chemosensitivity. Mechanistic investigations demonstrated that BRT sensitized PDAC cells to Gem by suppressing Nrf2 at the transcriptional level. Activation of Nrf2 conteracted BRT’s effects on chemosensitivity. In contrast, combination treatment with Nrf2 silencing and BRT demonstrated a more potent inhibitory effect on Gem in vitro and in vivo, thereby indicating the Nrf2 dependence of BRT action. These findings highlight BRT’s ability to enhance Gem chemosensitivity by inhibiting Nrf2 signaling in PDAC; therefore, BRT may serve as a potential adjuvant therapy for PDAC.

Macrophage infiltration in 3D cancer spheroids to recapitulate the TME and unveil interactions within cancer cells and macrophages to modulate chemotherapeutic drug efficacy

BackgroundRecapitulating the tumor microenvironment (TME) in vitro remains a major hurdle in cancer research. In recent years, there have been significant strides in this area, particularly with the emergence of 3D spheroids as a model system for drug screening and therapeutics development for solid tumors. However, incorporating macrophages into these spheroid cultures poses specific challenges due to the intricate interactions between macrophages and cancer cells.MethodsTo address this issue, in this study, we established a reproducible healthy multicellular 3D spheroid culture with macrophage infiltrates in order to mimic the TME and modulate the drug’s efficacy on cancer cells in the presence of macrophages. A 3D spheroid was established using the human cancer cell line CAL33 and THP1 cell derived M0 macrophages were used as a source of macrophages. Cellular parameters including tumour metabolism, health, and mitochondrial mass were analysed in order to establish ideal conditions. To modulate the interaction of cancer cells with macrophage the ROS, NO, and H2O2 levels, in addition to M1 and M2 macrophage phenotypic markers, were analyzed. To understand the crosstalk between cancer cells and macrophages for ECM degradation, HSP70, HIF1α and cysteine proteases were examined in spheroids using western blotting and qPCR.ResultsThe spheroids with macrophage infiltrates exhibited key features of solid tumors, including cellular heterogeneity, metabolic changes, nutrient gradients, ROS emission, and the interplay between HIF1α and HSP70 for upregulation of ECM degradading enzymes. Our results demonstrate that tumor cells exhibit a metabolic shift in the presence of macrophages. Additionally, we have observed a shift in the polarity of M0 macrophages towards tumor-associated macrophages (TAMs) in response to cancer cells in spheroids. Results also demonstrate the involvement of macrophages in regulating HIF-1α, HSP70, and ECM degradation cysteine proteases enzymes.ConclusionsThis study has significant implications for cancer therapy as it sheds light on the intricate interaction between tumor cells and their surrounding macrophages. Additionally, our 3D spheroid model can aid in drug screening and enhance the predictive accuracy of preclinical studies. The strength of our study lies in the comprehensive characterization of the multicellular 3D spheroid model, which closely mimics the TME.

Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system.

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration-approved gold-containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel-sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidaseand alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel-mediated cytotoxicity in a concentration-dependent manner in both MDA-MB-231 and MCF-7 cell lines. Moreover, auranofin increased the levelsof intracellular reactive oxygen species (observed using2, 7-diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine-123 staining) in a concentration-dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel-treated breast cancer cells compared to paclitaxel-alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy.

BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1

Checkpoint kinase 1 (CHK1), a key effector in the cellular response to DNA lesions, is a crucial component of all cell cycle checkpoints. Recent reports have revealed that CHK1 is highly expressed in numerous cancer types in the clinical settings. However, the mechanisms underlying the regulation of CHK1 expression in tumor cells remain unclear. Here, we report that CHK1 is negatively regulated by the bromodomain-containing protein 7 (BRD7). Specifically, BRD7 silencing increased CHK1 (but not CHK2) expression at both mRNA and protein levels, in a p53-independent manner in multiple tumor cell lines. Furthermore, BRD7 silencing stabilized CHK1 via reducing its ubiquitination. Mechanistically, BRD7 knockdown not only increased the levels of USP1, a deubiquitinase for CHK1, but also promoted the interaction between CHK1 and USP1, subsequently enhancing the de-ubiquitination of CHK1. USP1 knockdown abrogated BRD7 silencing-induced CHK1 induction. Biologically, the increased expression of CHK1 in tumor cells caused by BRD7 silencing significantly increased cell sensitivity to CHK1 inhibitors by enhancing tumor cell apoptosis, and this effect was reversed by the simultaneous knockdown of CHK1 or USP1. Taken together, our findings suggest that BRD7 is a potential genetic or drug target that may help to improve the efficacy of chemotherapeutic drugs targeting CHK1 in combinatorial therapy.

In Silico Exploration of Dietary Polyphenol, Bisdemethoxycurcumin as a Potential CXCL12 Inhibitor in Breast Cancer Treatment

Breast cancer stands as one of the most prevalent malignancies in women worldwide. The World Health Organization reported 2.3 million new cases and 685,000 fatalities due to breast cancer in 2020. In India alone, 162,468 new diagnoses and 87,090 deaths were recorded in 2018. CXCL12, also known as stromal cell-derived factor 1 (SDF-1), plays a significant role in tumor progression and metastasis in breast cancer, rendering it a promising target for intervention. Curcumin and its derivatives are known to inhibit breast cancer and enhance the efficacy of chemotherapeutic drugs. This study explores the potential of Bisdemethoxycurcumin, a synthesized derivative of curcumin, as a CXCL12 inhibitor in breast cancer. Our in-silico screening of Bisdemethoxycurcumin demonstrated a strong binding affinity to CXCL12, surpassing that of the reference compound, Plerixafor. We also compared our lead molecule with the reference compound (Plerixafor). Conversely, we observe that Bisdemethoxycurcumin shows a good binding affinity with the target protein and shows a strong bond interaction, particularly H-bond interaction in molecular docking and MD simulation studies both. Our findings identify Bisdemethoxycurcumin as a lead compound for future studies, necessitating validation through in vitro and in vivo investigations.

Divalent ions as mediators of carbonylation in cardiac myosin binding protein C

The dosing and efficacy of chemotherapeutic drugs can be limited by toxicity caused by off-pathway reactions. One hypothesis for how such toxicity arises is via metal-catalyzed oxidative damage of cardiac myosin binding protein C (cMyBP-C) found in cardiac tissue. Previous research indicates that metal ion mediated reactive oxygen species induce high levels of protein carbonylation, changing the structure and function of this protein. In this work, we use long timescale all-atom molecular dynamics simulations to investigate the ion environment surrounding the C0 and C1 subunits of cMyBP-C responsible for actin binding. We show that divalent cations are co-localized with protein carbonylation-prone amino acid residues and that carbonylation of these residues can lead to site-specific interruption to the actin-cMyBP-C binding.