The emerging role of the gut microbiome in cancer cell plasticity and therapeutic resistance.

Resistance to therapeutic agents is one of the major challenges in cancer therapy. Generally, the focus is given to the genetic driver, especially the genetic mutation behind the therapeutic resistance. However, non-mutational mechanisms, such as epigenetic modifications, and TME alteration, which is mainly driven by cancer cell plasticity, are also involved in therapeutic resistance. The concept of plasticity mainly relies on the conversion of non-cancer stem cells (CSCs) to CSCs or epithelial-to-mesenchymal transition via different mechanisms and various signaling pathways. Cancer plasticity plays a crucial role in therapeutic resistance as cancer cells are able to escape from therapeutics by shifting the phenotype and thereby enhancing tumor progression. New evidence suggests that gut microbiota can change cancer cell characteristics by impacting the mechanisms involved in cancer plasticity. Interestingly, gut microbiota can also influence the therapeutic efficacy of anticancer drugs by modulating the mechanisms involved in cancer cell plasticity. The gut microbiota has been shown to reduce the toxicity of certain clinical drugs. Here, we have documented the critical role of the gut microbiota on the therapeutic efficacy of existing anticancer drugs by altering the cancer plasticity. Hence, the extended knowledge of the emerging role of gut microbiota in cancer cell plasticity can help to develop gut microbiota-based novel therapeutics to overcome the resistance or reduce the toxicity of existing drugs. Furthermore, to improve the effectiveness of therapy, it is necessary to conduct more clinical and preclinical research to fully comprehend the mechanisms of gut microbiota.

The emerging role of miRNA in the perturbation of tumor immune microenvironment in chemoresistance: Therapeutic implications.

Chemoresistance is a major hindrance in cancer chemotherapies, a leading cause of tumor recurrence and cancer-related deaths. Cancer cells develop numerous strategies to elude immune attacks and are regulated by immunological factors. Cancer cells can alter the expression of several immune modulators to upregulate the activities of immune checkpoint pathways. Targeting the immune checkpoint inhibitors is a part of the cancer immunotherapy altered during carcinogenesis. These immune modulators have the capability to reprogram the tumor microenvironment, thereby change the efficacy of chemotherapeutics. In general, the sensitivity of drugs is reduced in the immunosuppressive tumor microenvironment, resulting in chemoresistance and tumor relapse. The regulation of microRNAs (miRNAs) is well established in cancer initiation, progression, and therapy. Intriguingly, miRNA affects cancer immune surveillance and immune response by targeting immune checkpoint inhibitors in the tumor microenvironment. miRNAs alter the gene expression at the post-transcriptional level, which modulates both innate and adaptive immune systems. Alteration of tumor immune microenvironment influences drug sensitivity towards cancer cells. Besides, the expression profile of immune-modulatory miRNAs can be used as a potential biomarker to predict the response and clinical outcomes in cancer immunotherapy and chemotherapy. Recent evidences have revealed that cancer-derived immune-modulatory miRNAs might be promising targets to counteract cancer immune escape, thereby increasing drug efficacy. In this review, we have compiled the role of miRNAs in overcoming the chemoresistance by modulating tumor microenvironment and discussed their preclinical and clinical implications.

Protective effect of diindolylmethane-enriched dietary cabbage against doxorubicin-induced cardiotoxicity in mice.

Chemotherapy with doxorubicin (Dox) can lead to cardiotoxic effects, presenting a major complication in cancer therapy. Diindolylmethane (DIM), derived from cruciferous vegetables like cabbage, exhibits numerous health benefits. However, its clinical application is limited because of low bioavailability and suboptimal natural concentrations in dietary sources. To address this limitation, we developed a processing methodology, specifically fermentation and boiling, to enhance DIM levels in cabbage. High-performance liquid chromatography (HPLC) analysis revealed a threefold DIM increase in fermented cabbage and a substantial ninefold increase in fermented-boiled cabbage compared to raw cabbage. To evaluate the clinical implications, we formulated a DIM-enriched diet and administered it to mice undergoing Dox treatment. Our in vivo results revealed that Dox treatment led to cardiotoxicity, manifested by changes in body and heart weight, increased mortality, and severe myocardial tissue degeneration. Dietary administration of the DIM-enriched diet enhanced antioxidant defenses and inhibited apoptosis in the cardiac tissue by interfering with mitoptosis and increasing antioxidant enzyme expression. Interestingly, we found that the DIM-enriched diet inhibited the nuclear translocation of NF-kB in cardiac tissue, thereby downregulating the expression of inflammatory mediators such as TNF-α and IL-6. Further, the DIM-enriched diet significantly reduced serum cardiac injury markers elevated by Dox treatment. These results suggest that the DIM-enriched cabbage diet can serve as a complementary dietary intervention for cancer patients undergoing chemotherapy. Further, our research highlights the role of plant-based diets in reducing treatment side effects and improving the quality of life for cancer patients.

Application of Oncolytic Poxviruses: An Emerging Paradigm in Cancer Therapy.

Despite the significant advancement of new tools and technology in the field of medical biology and molecular biology, the challenges in the treatment of most cancer types remain constant with the problem of developing resistance toward drugs and no substantial enhancement in the overall survival rate of cancer patients. Immunotherapy has shown the most promising results in different clinical and preclinical trials in the treatment of various cancer due to its higher efficacy and minimum collateral damage in many cancer patients as compared to conventional chemotherapy and radiotherapy. An oncolytic virus is a new class of immunotherapy that can selectively replicate in tumor cells and destroy them by the process of cell lysis while exerting minimum or no effect on a normal cell. Besides this, it can also activate the host's innate immune system, which generates an anti-tumor immune response to eliminate the tumor cells. Several wild types and genetically modified viruses have been investigated to show oncolytic behavior. Vaccinia virus has been studied extensively and tested for its promising oncolytic nature on various model systems and clinical trials. Recently, several engineered vaccinia viruses have been developed that express the desired genes encoded for selective penetration in tumor cells and enhanced activation of the immune system for generating anti-tumor immunity. However, further investigation is required to prove their potential and enhance their therapeutic efficacy.

Poxviruses as Agents of Biological Warfare: The Importance of Ensuring Ethical Standards for Research with Viruses.

Historically, biological agents have been used to target various populations. One of the earliest examples could be the catastrophic effect of smallpox in Australia in the eighteenth century (as alleged by some historians). Modern biological techniques can be used to both create or provide protection against various agents of biological warfare. Any microorganism (viruses, bacteria, and fungi) or its toxins can be used as biological agents. Minnesota Department of Health has listed Smallpox (variola major) as a category A bioterrorism agent, even though it has been eradicated in 1980 through an extensive vaccination campaign. Category A agents are considered the highest risk to public health. Laboratory-associated outbreaks of poxviruses could cause unprecedented occupational hazards. Only two WHO-approved BSL-4 facilities in the United States and Russia are allowed to perform research on the variola virus. So, poxviruses present themselves as a classical case of a dual-use dilemma, since research with them can be used for both beneficial and harmful purposes. Although the importance of ethics in scientific research requires no further elaboration, ethical norms assume greater significance during experimentation with poxviruses. In this chapter, we will update the readers on the sensitive nature of conducting research with poxviruses, and how these viruses can be a source of potential biological weapons. Finally, specified ethical guidelines are explored to ensure safe research practices in virology.

Progress and promises of epigenetic drugs and epigenetic diets in cancer prevention and therapy: A clinical update.

Epigenetic modifications are heritable yet reversible, essential for normal physiological functions and biological development. Aberrant epigenetic modifications, including DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation play a crucial role in cancer progression. In cellular reprogramming, irregular epigenomic modulations alter cell signaling pathways and the expression of tumor suppressor genes and oncogenes, resulting in cancer growth and metastasis. Therefore, alteration of epigenetic-status in cancer cells can be used as a potential target for cancer therapy. Several synthetic epigenetic inhibitors (epi-drugs) and natural epigenetic modulatory bioactives (epi-diets) have been shown to have the potential to alter the aberrant epigenetic status and inhibit cancer progression. Further, the use of combinatorial approaches with epigenetic drugs and diets has brought promising outcomes in cancer prevention and therapy. In this article, we have summarized the epigenetic modulatory activities of epi-drugs, epi-diets, and their combination against various cancers. We have also compiled the preclinical and clinical status of these epigenetic modulators in different cancers.

Dietary Diindolylmethane Enhances the Therapeutic Effect of Centchroman in Breast Cancer by Inhibiting Neoangiogenesis.

Tumor angiogenesis is primarily regulated by vascular endothelial growth factor and its receptor (VEGF-VEGFR) communication, which is involved in cancer cell growth, progression, and metastasis. Diindolylmethane (DIM), a dietary bioactive from cruciferous vegetables, has been extensively studied in preclinical models for breast cancer prevention and treatment. Nevertheless, the possible role of DIM in the angiogenesis and metastasis regulations in triple-negative breast cancer (TNBC) remains elusive. Here, we investigated the potential anti-angiogenic and anti-metastatic role of DIM in combination with centchroman (CC). We observed that the oral administration of the DIM and CC combination suppressed primary tumor growth and tumor-associated vascularization in 4T1 tumors. Further, the DIM and CC combination exhibited a strong inhibitory effect on VEGF-induced angiogenesis in matrigel plugs. The mechanistic study demonstrated that DIM and CC could effectively downregulate VEGFA expression in tumor tissue and strongly interact with VEGFR2 to block its kinase activity. Interestingly, the DIM and CC combination also suppressed the lung metastasis of the highly metastatic 4T1 tumors through the downregulation of FAK/MMP9/2 signaling and reversal of epithelial-to-mesenchymal transition (EMT). Overall, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating TNBC.

Mahanimbine isolated from Murraya koenigii inhibits P-glycoprotein involved in lung cancer chemoresistance.

P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.

Epigenetics of Breast Cancer: Clinical Status of Epi-drugs and Phytochemicals.

Epigenetics refers to alterations in gene expression due to differential histone modifications and DNA methylation at promoter sites of genes. Epigenetic alterations are reversible and are heritable during somatic cell division, but do not involve changes in nucleotide sequence. Epigenetic regulation plays a critical role in normal growth and embryonic development by controlling transcriptional activities of several genes. In last two decades, these modifications have been well recognized to be involved in tumor initiation and progression, which has motivated many investigators to incorporate this novel field in cancer drug development. Recently, growing number of epigenetic changes have been reported that are involved in the regulations of genes involved in breast tumor growth and metastasis. Drugs possessing epigenetic modulatory activities known as epi-drugs, mainly the inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Some of these drugs are undergoing different clinical trials for breast cancer treatment. Several phytochemicals such as green tea polyphenols, curcumin, genistein, resveratrol and sulforaphane have also been shown to alter epigenetic modifications in multiple cancer types including breast cancer. In this chapter, we summarize the role of epigenetic changes in breast cancer progression and metastasis. We have also discussed about various epigenetic modulators possessing chemopreventive and therapeutic efficacy against breast cancer with future perspectives.

ß-carotene at physiologically attainable concentration induces apoptosis and down-regulates cell survival and antioxidant markers in human breast cancer (MCF-7) cells.

Although ß-carotene is known for its anti-carcinogenic and antioxidant properties, a few recent epidemiological and experimental evidence show that at higher concentration it acts as pro-oxidant and induces cancer. Since the global burden of breast cancer exceeds all other types of cancer, and its incidence rates is also in increasing trend, the present study attempted to evaluate the anti-cancer molecular mechanism of ß-carotene (at 1 µM concentration) isolated from Spinacia oleracea in human breast cancer (MCF-7) cells. The carotenoid was purified by open column chromatography and identified by LC-MS. The anti-proliferative effect of ß-carotene at different concentrations was evaluated by WST-1 assay and the changes in cell morphology were examined by microscopic observation. The induction of apoptosis by ß-carotene was observed by DAPI staining and colorimetric caspase-3 assay. The expression of cell survival, apoptotic, and antioxidant marker proteins was measured by western blot analysis. Purified ß-carotene inhibited the viability of MCF-7 cells in a dose-dependent manner, which was well correlated with changes in cell morphology. Increased apoptotic cells were observed in ß-carotene (1 µM)-treated cells. This apoptosis induction was associated with increased caspase-3 activity. The protein expression studies showed that ß-carotene at 1 µM concentration effectively decreases the expression of the anti-apoptotic protein, Bcl-2 and PARP, and survival protein, NF-kB. It also inhibited the activation of intracellular growth signaling proteins, Akt and ERK1/2. The inhibition of Akt activation by ß-carotene results in decreased phosphorylation of Bad. Further, it down-regulated antioxidant enzyme, SOD-2, and its transactivation factor (Nrf-2), and endoplasmic reticulum (ER) stress marker, XBP-1, at protein levels. These findings exhibit the key role of ß-carotene even at a low physiological concentration in MCF-7 cells which further explains its predominant anti-cancer activity.

A whole-genome CRISPR screen identifies the spindle accessory checkpoint as a locus of nab-paclitaxel resistance in pancreatic cancer cells.

Pancreatic adenocarcinoma is one of the most aggressive and lethal forms of cancer. Chemotherapy is the primary treatment for pancreatic cancer, but resistance to the drugs used remains a major challenge. A genome-wide CRISPR interference and knockout screen in the PANC-1 cell line with the drug nab-paclitaxel has identified a group of spindle assembly checkpoint (SAC) genes that enhance survival in nab-paclitaxel. Knockdown of these SAC genes (BUB1B, BUB3, and TTK) attenuates paclitaxel-induced cell death. Cells treated with the small molecule inhibitors BAY 1217389 or MPI 0479605, targeting the threonine tyrosine kinase (TTK), also enhance survival in paclitaxel. Overexpression of these SAC genes does not affect sensitivity to paclitaxel. These discoveries have helped to elucidate the mechanisms behind paclitaxel cytotoxicity. The outcomes of this investigation may pave the way for a deeper comprehension of the diverse responses of pancreatic cancer to therapies including paclitaxel. Additionally, they could facilitate the formulation of novel treatment approaches for pancreatic cancer.

Disrupting the interaction between a p53 gain-of-function mutant and the transcriptional co-activator PC4 reverses drug resistance in cancer cells.

PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.

Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer.

Platinum-based drugs are the first line of therapeutics against many cancers, including lung cancer. Lung cancer is one of the leading causes of cancer-related death worldwide. Platinum-based agents target DNA and prevent replication, and transcription, leading to the inhibition of cell proliferation followed by cellular apoptosis. About twenty-three platinum-based drugs are under different stages of clinical trials, among cisplatin, carboplatin, and oxaliplatin are widely used for the treatment of various cancers. Among them, cisplatin is the most commonly used drug for cancer therapy, which binds with RNA, and hinders the cellular RNA process. However, long-term use of platinum-based drugs can cause different side effects and has been shown to develop chemoresistance, leading to poor clinical outcomes. Chemoresistance became an important challenge for cancer treatment. Platinum-based chemoresistance occurs due to the influence of intrinsic factors such as overexpression of multidrug resistance proteins, advancement of DNA repair mechanism, degradation, and deactivation of intracellular thiols. Recently, epigenetic modifications, especially non-coding RNAs (ncRNAs) mediated gene regulation, grasp the attention for reversing the sensitivity of platinum-based drugs due to their reversible nature without altering genome sequence. ncRNAs can also modulate the intrinsic and non-intrinsic mechanisms of resistance in lung cancer cells. Therefore, targeting ncRNAs could be an effective approach for developing novel therapeutics to overcome lung cancer chemoresistance. The current review article has discussed the role of ncRNA in chemoresistance and its underlying molecular mechanisms in human lung cancer.

The long-term impact of coronavirus disease 2019 on environmental health: a review study of the bi-directional effect.

Background: When health systems worldwide grapple with the coronavirus disease 2019 (COVID-19) pandemic, its effect on the global environment is also a significant consideration factor. It is a two-way process where the pre-COVID climate factors influenced the landscape in which the disease proliferates globally and the consequences of the pandemic on our surroundings. The environmental health disparities will also have a long-lasting effect on public health response. Main body: The ongoing research on the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 must also include the role of environmental factors in the process of infection and the differential severity of the disease. Studies have shown that the virus has created positive and negative ramifications on the world environment, especially in countries most critically affected by the pandemic. Contingency measures to slow down the virus, such as self-distancing and lockdowns have shown improvements in air, water, and noise quality with a concomitant decrease in greenhouse gas emissions. On the other hand, biohazard waste management is a cause for concern that can result in negative effects on planetary health. At the peak of the infection, most attention has been diverted to the medical aspects of the pandemic. Gradually, policymakers must shift their focus to social and economic avenues, environmental development, and sustainability. Conclusion: The COVID-19 pandemic has profoundly impacted the environment, both directly and indirectly. On the one hand, the sudden halt in economic and industrial activities led to a decrease in air and water pollution, as well as a reduction in greenhouse gas emissions. On the other hand, the increased use of single-use plastics and a surge in e-commerce activities have had negative effects on the environment. As we move forward, we must consider the pandemic's long-term impacts on the environment and work toward a more sustainable future that balances economic growth and environmental protection. The study shall update the readers on the various facets of the interaction between this pandemic and environmental health with model development for long-term sustainability.

Use of CRISPR-based screens to identify mechanisms of chemotherapy resistance.

Despite the development of new classes of targeted anti-cancer drugs, the curative treatment of metastatic solid tumors remains out of reach owing to the development of resistance to current chemotherapeutics. Although many mechanisms of drug resistance have been described, there is still a general lack of understanding of the many means by which cancer cells elude otherwise effective chemotherapy. The traditional strategy of isolating resistant clones in vitro, defining their mechanism of resistance, and testing to see whether these mechanisms play a role in clinical drug resistance is time-consuming and in many cases falls short of providing clinically relevant information. In this review, we summarize the use of CRISPR technology, including the promise and pitfalls, to generate libraries of cancer cells carrying sgRNAs that define novel mechanisms of resistance. The existing strategies using CRISPR knockout, activation, and inhibition screens, and combinations of these approaches are described. In addition, specialized approaches to identify more than one gene that may be contributing to resistance, as occurs in synthetic lethality, are described. Although these CRISPR-based approaches to cataloguing drug resistance genes in cancer cells are just beginning to be utilized, appropriately used they promise to accelerate understanding of drug resistance in cancer.

Extract of Murraya koenigii selectively causes genomic instability by altering redox-status via targeting PI3K/AKT/Nrf2/caspase-3 signaling pathway in human non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Dietary bioactives have been used as alternative therapeutics to overcome various adverse effects caused by chemotherapeutics. Curry leaves are a widely used culinary spice and different parts of this plant have been used in traditional medicines. Curry leaves are a rich source of multiple bioactives, especially polyphenols and alkaloids. Therefore, extraction processes play a key role in obtaining the optimum yield of bioactives and their efficacy. PURPOSE: We aim to select an extraction process that achieves the optimum yield of bioactives in curry leaves crude extract (CLCE) with minimum solvent usage and in a shorter time. Further, to investigate the anticancer properties of CLCE and its mechanism against lung cancer. METHODS: Different extraction processes were performed and analyzed polyphenol content. The bioactives and essential oils present in curry leaves were identified through LC-MS/MS and GC-MS analysis. The cytotoxicity of microwave-assisted CLCE (MA-CLCE) was investigated through MTT and colony-forming assays. The DNA damage was observed by comet assay. The apoptotic mechanisms of MA-CLCE were investigated by estimating ROS production, depolarization of mitochondrial membrane potential (MMP), and apoptotic proteins. The glutathione assay estimated the antioxidant potential of MA-CLCE in normal cells. RESULTS: Generally, conventional extraction methods require high temperatures, extra energy input, and time. Recently, green extraction processes are getting wider attention as alternative extraction methods. This study compared different extraction processes and found that the microwave-assisted extraction (MAE) method yields the highest polyphenols from curry leaves among other extraction processes with minimum processing. The MA-CLCE functions as an antioxidant under normal physiological conditions but pro-oxidant to cancer cells. MA-CLCE scavenges free radicals and enhances the intracellular GSH level in alveolar macrophages in situ. We found that MA-CLCE selectively inhibits cell proliferation and induces apoptosis in cancer cells by altering cellular redox status. MA-CLCE induces chromatin condensation and genotoxicity through ROS-induced depolarization of MMP. The depolarization of MMP causes the release of cytochrome c into the cytosol and activates the apoptotic pathway in lung cancer cells. However, pretreatment with ascorbic acid, an antioxidant, inhibits the MA-CLCE-induced apoptosis by reducing ROS production, which impedes mitochondrial membrane disruption, preventing BAX/BCL-2 expression alteration. Simultaneously, MA-CLCE downregulates the expression of survival signaling regulator PI3K/AKT, which modulates Nrf-2. MA-CLCE also diminishes intracellular antioxidant proficiency by suppressing Nrf-2 expression, followed by HO-1 expressions. CONCLUSION: Among several extraction methods, MA-CLCE is rich in several bioactives, especially polyphenols, alkaloids, and essential oils. Here, we reported for the first time that MA-CLCE functions as a pro-oxidant to lung cancer cells and acts as an antioxidant to normal cells by regulating different cellular programs and signaling pathways. Therefore, it can be further developed as a promising phytomedicine against lung cancer.

Traditional medicinal plants against replication, maturation and transmission targets of SARS-CoV-2: computational investigation.

COVID-19 is an infectious pandemic caused by the SARS-CoV-2 virus. The critical components of SARS-CoV-2 are the spike protein (S-protein) and the main protease (Mpro). Mpro is required for the maturation of the various polyproteins involved in replication and transcription. S-protein helps the SARS-CoV-2 to enter the host cells through the angiotensin-converting enzyme 2 (ACE2). Since ACE2 is required for the binding of SARS-CoV-2 on the host cells, ACE2 inhibitors and blockers have got wider attention, in addition to S-protein and Mpro modulators as potential therapeutics for COVID-19. So far, no specific drugs have shown promising therapeutic potential against COVID-19. The current study was undertaken to evaluate the therapeutic potential of traditional medicinal plants against COVID-19. The bioactives from the medicinal plants, along with standard drugs, were screened for their binding against S-protein, Mpro and ACE2 targets using molecular docking followed by molecular dynamics. Based on the higher binding affinity compared with standard drugs, bioactives were selected and further analyzed for their pharmacological properties such as drug-likeness, ADME/T-test, biological activities using in silico tools. The binding energies of several bioactives analyzed with target proteins were relatively comparable and even better than the standard drugs. Based on Lipinski factors and lower binding energies, seven bioactives were further analyzed for their pharmacological and biological characteristics. The selected bioactives were found to have lower toxicity with a higher GI absorption rate and potent anti-inflammatory and anti-viral activities against targets of COVID-19. Therefore, the bioactives from these medicinal plants can be further developed as phytopharmaceuticals for the effective treatment of COVID-19.Communicated by Ramaswamy H. Sarma.

Diindolylmethane Promotes Metabolic Crisis and Enhances the Efficacy of Centchroman in Breast Cancer: A 1H NMR-Based Approach.

Diindolylmethane (DIM) is a key metabolite of indole-3-carbinol found in cruciferous vegetables such as broccoli, cauliflower, and cabbage. DIM has been known for its anti-cancerous activity through various mechanisms. Most cancer cells, including triple-negative breast cancer (TNBC), adapt distinct metabolic reprogramming for rapid growth and proliferation. Hence, targeting metabolic dysregulation may provide a favorable therapeutic condition for the treatment of TNBC. Earlier, we found that DIM increases the intracellular accumulation of Centchroman (CC), a potential anticancer agent, thereby enhancing the therapeutic potential of CC against breast cancer. However, the role of DIM in regulating TNBC cellular metabolism remains unknown. In the current study, we investigated the potential therapeutic interventions of DIM in TNBC and its metabolic reprogramming in enhancing the efficacy of CC. We found that DIM induced metabolic catastrophe in TNBC cells by regulating aerobic glycolysis and intermediate metabolism. Further, the DIM and CC combination significantly inhibited the TNBC tumor growth in the 4T1-syngeneic model. The inhibition of tumor growth was associated with the downregulation of key aerobic glycolysis mediators such as PKM2, GLUT1, and hypoxia-inducible factor 1α (HIF-1α). This is a first-of-a-kind investigation linking DIM with aerobic glycolysis regulation and enhancing the treatment efficacy of CC against TNBC. Therefore, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating metabolically dysregulated TNBC.

microRNAs in cancer chemoresistance: The sword and the shield.

Cancer is a multifactorial disease and one of the leading causes of mortality worldwide. Cancer cells develop multiple strategies to reduce drug sensitivity and eventually lead to chemoresistance. Chemoresistance is initiated either by intrinsic factors or due to the prolonged use of chemotherapeutics as acquired resistance. Further, chemoresistance is also one of the major reasons behind tumor recurrence and metastasis. Therefore, overcoming chemoresistance is one of the primary challenges in cancer therapy. Several mechanisms are involved in chemoresistance. Among them, the key role of ABC transporters and tumor microenvironment have been well studied. Recently, microRNAs (miRNAs) regulation in tumor development, metastasis, and chemotherapy has got wider interest due to its role in regulating genes involved in cancer progression and therapy. Noncoding RNAs, including miRNAs, have been associated with the regulation of tumor-suppressor and tumor-promoter genes. Further, miRNA can also be used as a reliable diagnostic and prognostic marker to predict the stage and types of cancer. Recent evidences have revealed that miRNAs regulation also influences the function of drug transporters and the tumor microenvironment, which affects chemosensitivity to cancer cells. Therefore, miRNAs can be a promising target to reverse back chemosensitivity in cancer cells. This review comprehensively discusses the mechanisms involved in cancer chemoresistance and its regulation by miRNAs.

Dietary bioactive diindolylmethane enhances the therapeutic efficacy of centchroman in breast cancer cells by regulating ABCB1/P-gp efflux transporter.

Overexpression of drug efflux transporters is commonly associated with multidrug-resistance in cancer therapy. Here for the first time, we investigated the ability of diindolylmethane (DIM), a dietary bioactive rich in cruciferous vegetables, in enhancing the efficacy of Centchroman (CC) by modulating the drug efflux transporters in human breast cancer cells. CC is a selective estrogen receptor modulator, having promising therapeutic efficacy against breast cancer. The combination of DIM and CC synergistically inhibited cell proliferation and induced apoptosis in breast cancer cells. This novel combination has also hindered the stemness of human breast cancer cells. Molecular docking analysis revealed that DIM had shown a strong binding affinity with the substrate-binding sites of ABCB1 (P-gp) and ABCC1 (MRP1) drug-efflux transporters. DIM has increased the intracellular accumulation of Hoechst and Calcein, the substrates of P-gp and MRP1, respectively, in breast cancer cells. Further, DIM stimulates P-gp ATPase activity, which indicates that DIM binds at the substrate-binding domain of P-gp, and thereby inhibits its efflux activity. Intriguingly, DIM enhanced the intracellular concentration of CC by inhibiting the P-gp and MRP1 expression as well as activity. The intracellular retaining of CC has increased its efficacy against breast cancer. Overall, DIM, a dietary bioactive, enhances the anticancer efficiency of CC through modulation of drug efflux ABC-transporters in breast cancer cells. Therefore, DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy against human breast cancer.