Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer and is frequently resistant to therapy, ultimately resulting in treatment failure. Clinical trials have demonstrated the potential of sensitizing radiation therapy (RT)-resistant TNBC through the combination of chemotherapy and RT. This study sought to explore the potential of CD151 as a therapy response marker in the co-treatment strategy involving ionizing radiation (IR) and the repurposed antiviral drug 2-Thio-6-azauridine (TAU) for sensitizing RT-resistant TNBC (TNBC/RR). The investigation encompassed a variety of assessments, including viability using MTT and LDH assays, cell proliferation through BrdU incorporation and clonogenic assays, cell cycle analysis via flow cytometry, cell migration using wound scratch and Boyden chamber invasion assays, DNA damage assessment through γH2AX analysis, apoptosis evaluation through acridine-orange and ethidium bromide double staining assays, as well as caspase 3 activity measurement using a colorimetric assay. CD151 expression was examined through ELISA, flow cytometry and RT-qPCR. The results showed a significant reduction in TNBC/RR cell viability following co-treatment. Moreover, the co-treatment reduced cell migration, induced apoptosis, downregulated CD151 expression, and increased caspase 3 activity in TNBC/RR cells. Additionally, CD151 was predicted to serve as a therapy response marker for co-treatment with TAU and IR. These findings suggest the potential of combination treatment with IR and TAU as a promising strategy to overcome RT resistance in TNBC. Furthermore, CD151 emerges as a valuable therapy response marker for chemoradiotherapy.

Triple-negative breast cancer is high heterogeneous, aggressive, and metastatic with poor prognosis. Despite of advances in targeted therapies, TNBC has been reported to cause high morbidity and mortality. A rare subpopulation within the tumor microenvironment organized into a hierarchy of cancer stem cells is responsible for therapy resistance and tumor recurrence. Repurposing of antiviral drugs for cancer treatment is gaining momentum due to reduced cost, labour, and research time, but limited due to lack of prognostic, and predictive markers. The present study investigates proteomic profiling and ROC analysis to identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug 2-thio-6-azauridine (TAU) in resistant TNBC. The stemness of MDA-MB 231 and MDA-MD 468 adherent cells was enriched by culturing them under non-adherent and non-differentiation conditions. Then, CD151+ subpopulation was isolated and characterized for the enrichment of stemness. This study found that CD151 has overexpressed in stemness enriched subpopulations, and also showed CD44 high and CD24 low expression along with stem cell-related transcription factors octamer-binding transcription factor 4 (OCT4) and Sex determining Y-box 2 (SOX2). This study also found that TAU induced significant cytotoxicity and genotoxicity in the CD151+TNBC subpopulation and inhibited their proliferation by inducing DNA damage, cell cycle arrest at the G2M phase, and apoptosis. Further, a proteomic profiling study showed that the expression of CD151 along with ELAVL1, an RNA-binding protein, was significantly reduced with TAU treatment. KM plotter showed correlation of CD151 and ELAVL1 gene expression with a poor prognosis of TNBC. ROC analysis predicted and validated CD151 and ELAVL1 as best therapy response marker for TAU in TNBC. These findings provide new insight into repurposing antiviral drug TAU for treatment of metastatic and drug resistant TNBC.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype of breast cancer. This tumorigenicity is independent of hormonal or HER2 pathways because of a lack of respective receptor expression. TNBC is extremely prone to drug resistance and early recurrence because of T-regulatory cell (Treg) infiltration into the tumor microenvironment (TME) in addition to other mechanisms like genomic instability. Tumor-infiltrating Tregs interact with both tumor and stromal cells as well as extracellular matrix components in the TME and induce an immune-suppressive phenotype. Hence, treatment of TNBC with conventional therapies remains challenging. Understanding the protective mechanism of Tregs in shielding TNBC from antitumor immune responses in the TME will pave the way for developing novel, immune-based therapeutics. The current review focuses on the role of tumor-infiltrating Tregs in tumor progression and metabolic reprogramming of the TME. The authors have extended their focus to oncotargeting Treg-mediated immune suppression in breast cancer. Because of its potential role in the TME, modulating Treg activity may provide a novel strategic intervention to combat TNBC. Both under laboratory conditions and in clinical trials, currently available anticancer drugs and natural therapeutics as potential agents for targeting Tregs are explored.

The microbiome assisted tumor microenvironment (TME) supports the tumors by modulating multiple mechanisms. Recent studies reported that microbiome dysbiosis is the main culprit of immune suppressive phenotypes of TME. Further, it has been documented that immune suppressive stimulate metastatic phenotype in TME via modulating signaling pathways, cell differentiation, and innate immune response. This review aims at providing comprehensive developments in microbiome and breast TME interface. The combination of microbiome and breast cancer, breast TME and microbiome or microbial dysbiosis, microbiome and risk of breast cancer, microbiome and phytochemicals or anticancer drugs were as used keywords to retrieve literature from PubMed, Google scholar, Scopus, Web of Science from 2015 onwards. Based on the literature, we presented the impact of TME assisted microbiome dysbiosis and estrobolome in breast cancer risk, drug resistance, and antitumor immunity. We have discussed the influence of antibiotics on the breast microbiome. we also presented the possible dietary phytochemicals that target microbiome dysbiosis to restore the tumor suppression immune environment in breast TME. We presented the microbiome as a possible marker for breast cancer diagnosis. This study will help in the identification of microbiome as a novel target and diagnostic markers and phytochemicals and microbiome metabolites for breast cancer treatment.

Background: 2-thio-6-azauridine (TAU) is a nucleoside analog and potential antiviral drug. The antiproliferative activity of TAU has been evaluated in limited cancer cell lines. The present study is aimed to evaluate the effect of TAU on drug sensitization mechanism in paclitaxel (PTX) resistant triple-negative breast cancer (TNBC) cells.Methods: The cell death mechanism was determined using MTT, BrdU incorporation, apoptosis, and DNA damage Western blot and RT-PCR assays. A specific ELISA method was used to determine the caspase-3 activity and expression levels of MRP1, MDR1, BCRP, and MRP8. Western blot analysis was used to assess the expression of CD151, MRP1, MDR1, and BCRP in CD151 overexpressing PTX-resistant TNBC cells.Results: The combination of TAU and PTX (10:20nM) synergistically inhibited the 50% viability of 12-fold PTX-resistant TNBC cells. Mechanistically, the combination inhibited the proliferation by arresting the cell cycle at the G2M phase and induced apoptosis by altering cell integrity and nuclear morphology as well as damaging DNA. The combination sensitized the PTX-resistant TNBC cells by increasing BAX and decreasing Bcl-2 expression, activating caspase-3, and reducing the expression of ABC transporters MRP1 and MDR1. The combination reduced the expression of MRP1 and MDR1 in CD151 overexpressing PTX-resistant TNBC cells, indicating the role of CD151in TAU mediated sensitization of PTX-resistant TNBC cells. The combination also reduced the mammosphere formation efficiency of PTX-resistant TNBC cells. Conclusion: Overall, the present study illustrated the promising ability of TAU in sensitizing drug-resistant TNBC cells to PTX.

Hepatocellular carcinoma (HCC) is a highly metastatic and drug-resistant lethal malignancy due to a heterogeneous tumor microenvironment. Pathologically, HCC is induced by hepatitis B virus and hepatitis C virus infection, alcohol consumption, exposure to aflatoxins, cigarette smoke and use of contraceptives, type 2 diabetes, and nonalcoholic fatty liver disease. Additionally, the risk of HCC is enhanced by intratumoral heterogeneity and clonal evaluation. However, long-term use of plant-based secondary metabolites and natural compounds reduces the risk of HCC. Therefore understanding the mechanisms that are accountable for intrinsic drug resistance and the cellular and molecular pathways that are associated with inherent drug resistance is of primary importance for developing novel approaches for HCC treatment. This book chapter covers pathways mediated by reactive oxygen species (ROS) in HCC biology and therapy. ROS-mediated mechanisms that are involved in the inherent drug resistance are also discussed, as are ROS-generating natural products for the treatment of HCC. Therefore comprehensive insight into ROS-mediated pathways will be useful in developing HCC therapeutics.

Ethnopharmacological relevance: Ayurvedic practitioners and herbal healers in India and China have extensively used garlic (Allium sativum L.) to treat cancers. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are major volatile organosulfur phytochemical constituents found in garlic. Aim of the study: To find new insight into the drug sensitizing effect of DADS and DATS on paclitaxel (PTX)resistant triple-negative breast cancer cells (TNBC/PR). Materials and methods: This study estimates the non-toxic concentration of DADS and DATS against normal healthy breast epithelial cell line (MCF-12A) by using a trypan blue viability assay. Also, it evaluates the effect of DADS and DATS on the sensitization of established stable TNBC/PR cell clones (MDA-MB 231 PR and MDA-MB 468 PR) by MTT, BrdU incorporation, intracellular ROS, cell cycle, and apoptosis assays. Results: The results show that DADS and DATS are non-cytotoxicity against MCF-12A cells. Nevertheless, DADS and DATS have shown significantly high cytotoxicity against MDA-MB 231 PR and MDA-MB 468 PR cells. They also inhibited PTX-resistant cell proliferation by blocking the cell cycle. Further, they induced apoptosis by activation of caspase 3 and 9. N-acetyl cysteine pre-treatment inhibited DADS and DATS-induced intracellular ROS release. In silico study shows that DADS and DATS interact with a large extracellular loop (LEL) of CD151 with a binding energy of -4.0 kcal/mol and transmembrane domain (TM) with a binding affinity of 11.7 and 13.6 kcal/mol, respectively. They also inhibited the surface expression of CD151 in TNBC/PR cells. Conclusion: This study implies that DADS and DATS could be considered for sensitizing drug-resistant breast cancers.

Background: The oncogenic tetraspanins CD9, CD 63, CD 81, CD151, and Tspan 8 have been recognized as critical mediators of cellular functions and malignant molecular mechanisms of human cancers. They support metastasis, drug resistance, and stem cell maintenance by interacting with other tetraspanins, receptors, and signaling molecules. Targeting tetraspanins have been proven to be efficient in destroying cancer cells and in blocking metastasis. Breast, ovarian, and cervical cancers are leading cancers among the top ten cancer in women. Their treatment is highly challenging due to the lack of early diagnostic markers and potential targets of drug resistance mechanisms. Purpose: To review the recent updates on oncogenic tetraspanin-mediated metastasis, drug resistance, and maintenance of stem cells, as well as their potentiality in the treatment and diagnosis of cancers in females. Discussion: This review discussed the role of oncogenic tetraspanins in regulating signaling pathways of metastasis. We also discussed their role in maintaining stem cells and drug resistance. Finally, we elaborated on their relevance in treating and diagnosing cancers in females. Conclusion: This study could help identify promising tetraspanins, which can be implicated in the early diagnosis and treatment of cancers in females.

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.

Background: Lung cancer is a significant health concern worldwide due to high mortality and morbidity, despite the advances in diagnosis, treatment, and management. Recent experimental evidence from different models suggested long non-coding RNAs (lncRNAs) as major modulators of cancer stem cells (CSCs) in the tumor microenvimnment (TME) to support metastasis and drug resistance in lung cancer. Evidence-based studies demonstrated that natural products interfere with TME functions. Purpose of study: To establish lncRNAs of TME as novel targets of natural compounds for lung cancer management. Study design: Current study used a combination of TME and lung CSCs, lncRNAs and enrichment and stemness maintenance, natural products and stem cell management, natural products and lncRNAs, natural products and targeted delivery as keywords to retrieve the literature from Scopus, Web of Science, PubMed, and Google Scholar. This study critically reviewed the current literature and presented cancer stem cells' ability in reprogramming lung TME. Results: This review found that TME related oncogenic and tumor suppressor lncRNAs and their signaling pathways control the maintenance of stemness in lung TME. This review explored natural phenolic compounds and found that curcumin, genistein, quercetin epigallocatechin gallate and ginsenoside Rh2 are efficient in managing lung CSCs. They modulate lncRNAs and their upstream mediators by targeting signaling and epigenetic pathways. This review also identified relevant nanotechnology-based phytochemical delivery approaches for targeting lung cancer. Conclusion: By critical literature analysis, TME related lncRNAs were identified as potential therapeutic targets, aiming to develop natural product-based therapeutics to treat metastatic and drug-resistant lung cancers.

Triple-negative breast cancer (TNBC) is a highly lethal and aggressive subtype of breast cancer (BC). A unique molecular signature, lack of specific targets, and the hostile tumor microenvironment make TNBC less responsive to existing chemotherapeutics. Recent studies have extensively reported long non-coding RNAs (lncRNAs) as critical mediators of cellular and molecular mechanisms of BC development and metastasis. They regulate genes at transcrip-tional, post-transcriptional, and translational levels by targeting key molecules and signaling mechanisms. This review aims to present oncogenic lncRNAs as promising targets of BC therapy. It primarily updated the current knowledge of the biology, types, and biogenesis of lncRNAs. This study used a combination of cancer stem cells and BCs, lncRNAs and BC development, lncRNAs and BC metastasis, lncRNAs, and targeted therapeutics as key words to retrieve the literature from Scopus, Web of Science, PubMed, and Google Scholar from 2015-2021. This review includes studies on the expression, diagnostic and prognostic importance, clinical trials, meta-analysis regarding lncRNAs and BC and excludes all abstracts and conference proceedings. We also present the association of lncRNAs and cellular and molecular mechanisms of cancer and their functional roles in BC development. The molecular mechanisms of major oncogenic lncRNAs H19, HOTAIR, and MALAT1 in BC metastasis and their targeting strategies using plant-derived natural compounds, small-molecule drugs, and RNA interference molecules are summarized. This review provides novel ideas for the development of targeted therapeutics for anti-lncRNA therapy of BC.

Objective: In the present modern era of time, poor and frantic lifestyle has led to an enumerate increase in the number of people with obesity and metabolic syndrome (MS). Epidemiological studies have shown the incidence of chronic kidney disease (CKD) risk factors in individuals with obesity and MS; despite the nonclear evidence on the existing potential risk factors, it became important to reassess existing potential risk factors that are involved in disease progression and its further complications. The strongest risk factor of CKD, albumin-to-creatinine ratio (ACR) recognized as a marker of MS and obesity. This study was carried out to identify the association of obesity (body mass index [BMI]) as a risk factor for albuminuria and to observe the dependence and association with albuminuria of each critical and basic factor of MS. Design: We conducted the potential risk factor analysis on 913 subjects, including 398 females and 515 males, from various diabetic hospitals of Vijayawada, Andhra Pradesh from early 2013 to June 2015. The medical records of the patients followed up; the anthropometric measurements and clinical parameters were retrospectively collected. The total subjects were categorized as subjects with and without MS as per National Cholesterol Education Program Adult Treatment Panel (NCEP-ATPIII) and the subjects with BMI more than 30 kg/m2 were defined as obese according to WHO classification. Results: Student’s t test analysis indicates a significant difference for ACR with mean values of 39.5 ± 44.8 and 18.4 ± 24.3 (P < 0.0001) in subjects with MS and without MS, 43.4 ± 48.3 and 36.7 ± 42.5 (P < 0.02) in obese and nonobese subjects, respectively. Chi-square analysis showed a significant association (P < 0.05) between MS and ACR and correlation analysis manifested significant association (P < 0.01) between ACR and FBS, TG, B.P, and Age in subjects with MS. The subjects with high prevalence of albuminuria exhibited significant association with an odds ratio (OR) of 1 (referent) 1.9 (95% CI, 1.34–2.58, P = 0.0002), 1.5 (95% CI, 1.11–1.96, P = 0.0082) for FBS >110 mg/dL, and TG > 150 mg/dL, respectively. Although the subjects with obesity showed no correlation with albuminuria, the risk for albuminuria was 1.5 times (95%CI 1.03–2.40, P = 0.03) higher among obese male subjects compared to obese female subjects. Conclusion: Our study strongly supports that albuminuria is highly prevalent among the subjects, with MS showing a significant positive association between obesity (BMI) with albuminuria in males only.

Colon cancer (CC) is the third most common cancer diagnosed worldwide, making it a serious global challenge. Metastasis is mainly responsible for high mortality in CC patients. In CC patients, a mutation in Kirsten rat sarcoma (KRAS), adenomatous polyposis coli (APC), and tumor protein 53 (TP53) mainly drives the metastasis, mediates drug resistance, and promotes tumor recurrence by maintaining stem cell phenotype. Recently, long noncoding RNAs (lncRNAs) were reported to mediate KRAS-, APC-, and TP53-dependent CC progression and metastasis. In the present review, we have discussed the current updates on lncRNAs dependent on KRAS, APC, and TP53 in CC progression and metastasis. We also presented current trends in targeted therapies, immune therapies, redox-based therapies, and phytochemical-based therapies for CC. Finally, nanosystems for targeted delivery of therapeutic agents, which limit drug resistance and drug toxicities, were discussed. Therefore, targeted therapeutics can be used for CC treatment at the clinical stage.

Colon cancer (CC) is the third most diagnosed cancers globally and second most lethal malignancy in both men and women due to aggressive metastatic ability. Genetic or somatic mutations causes the transformation of normal epithelium of colon into precancerous stage and eventually to metastatic phenotype in nearly 10 to 15 years. This progression is depending heavily on the tumor induced angiogenesis, which significantly impact the survival of the patients. Angiogenesis is majorly promoted by hypoxia, growth factors, macrophages, and non-coding RNAs as well as distinct signaling pathways in metastatic CCs. Blocking of antiangiogenic pathway using phytochemicals, small molecules, synthetic derivatives alone or along with chemotherapeutics substantially enhanced disease control as well as overall survival of patients with metastatic CC in second line treatment. Further, clinical trials showed benefit of adjuvant chemotherapeutics for treating metastatic CC patients. This chapter attempts to summarize the recent updates of angiogenic promotes of metastatic CC and targeted therapeutics for adjuvant therapy in clinical trials.