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Multiple myeloma (MM) is a hematologic malignancy associated with malignant plasma cell proliferation in the bone marrow. Despite the available treatments, drug resistance and adverse side effects pose significant challenges, underscoring the need for alternative therapeutic strategies. Natural products, like the fungal metabolite neosetophomone B (NSP-B), have emerged as potential therapeutic agents due to their bioactive properties. Our study investigated NSP-B's antitumor effects on MM cell lines (U266 and RPMI8226) and the involved molecular mechanisms. NSP-B demonstrated significant growth inhibition and apoptotic induction, triggered by reduced AKT activation and downregulation of the inhibitors of apoptotic proteins and S-phase kinase protein. This was accompanied by an upregulation of p21Kip1 and p27Cip1 and an elevated Bax/BCL2 ratio, culminating in caspase-dependent apoptosis. Interestingly, NSP-B also enhanced the cytotoxicity of bortezomib (BTZ), an existing MM treatment. Overall, our findings demonstrated that NSP-B induces caspase-dependent apoptosis, increases cell damage, and suppresses MM cell proliferation while improving the cytotoxic impact of BTZ. These findings suggest that NSP-B can be used alone or in combination with other medicines to treat MM, highlighting its importance as a promising phytoconstituent in cancer therapy., (© 2023 The Authors. Cell Biology International published by John Wiley & Sons Ltd on behalf of International Federation of Cell Biology.)

Cancer remains one of the leading causes of mortality worldwide, presenting a significant healthcare challenge owing to the limited efficacy of current treatments. The application of nanotechnology in cancer treatment leverages the unique optical, magnetic, and electrical attributes of nanomaterials to engineer innovative, targeted therapies. Specifically, manipulating nanomaterials allows for enhanced drug loading efficiency, improved bioavailability, and targeted delivery systems, reducing the non-specific cytotoxic effects characteristic of conventional chemotherapies. Furthermore, recent advances in nanotechnology have demonstrated encouraging results in specifically targeting CSCs, a key development considering the role of these cells in disease recurrence and resistance to treatment. Despite these breakthroughs, the clinical approval rates of nano-drugs have not kept pace with research advances, pointing to existing obstacles that must be addressed. In conclusion, nanotechnology presents a novel, powerful tool in the fight against cancer, particularly in targeting the elusive and treatment-resistant CSCs. This comprehensive review delves into the intricacies of nanotherapy, explicitly targeting cancer stem cells, their markers, and associated signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Colon cancer (CRC) is the second leading cause of death and the third most diagnosed cancer worldwide. Although curcumin (CUR) has demonstrated a potent anticancer activity, it is characterized by its poor solubility, low bioavailability, and instability. This study is a projection from a previous investigation where CUR and succinylated CUR (CUR.SA) were separately encapsulated in mannosylated-chitosan nanoparticles (CM-NPs) to form CUR-NPs and CUR.SA-NPs, respectively. Here, we aim to assess the anti-CRC activity of these two nanoformulations. Cytotoxicity studies using CCK-8 assay indicated that both CUR-NPs and CUR.SA-NPs have a dose and time-dependent toxicity towards CRC human cell-lines (HCT116 and SW480), and more cytotoxic compared to free CUR or CUR-SA in a time-dependent manner. A significant induction of early and late apoptosis in the CUR-NPs and CUR.SA-NPs treated CRC cell lines compared to untreated cells was observed. Western blotting analyses confirmed the induction of apoptosis through activation of Caspase signaling compared to untreated cells. Based on the physicochemical properties of CUR-NPs and CUR.SA-NPs along with the data from the in vitro studies, we may conclude these nanoparticle formulations hold very promising attributes, worthy of further investigations for its role in the management of CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer., Competing Interests: Conflict of interest statement All the authors meet the criteria for authorship. This manuscript is not under consideration for publication elsewhere. Every author is aware of, has agreed to this paper's content, and is listed as an author on the paper. All the authors declared no potential conflict of interest involved with this work., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The journal of APJCP (Asian Pacific Journal of Cancer Prevention) focuses to gather relevant and up-to-date novel information's related to cancer sciences. The research methodologies and approaches adopted by the researcher are prone to variation which may be desirable in the context of novel scientific findings however, the reproducibility for these studies needs to be unified and assured. The reproducibility issues are highly concerned when preclinical studies are reported in cancer, for natural products in particular. The natural products and medicinal plants are prone to a wide variation in terms of phytochemistry and phyto-pharmacology, ultimately affecting the end results for cancer studies. Hence the need for specific guidelines to adopt a best-practice in cancer research are utmost essential. The current AIMRDA guidelines aims to develop a consensus-based tool in order to enhance the quality and assure the reproducibility of studies reporting natural products in cancer prevention. A core working committee of the experts developed an initial draft for the guidelines where more focus was kept for the inclusion of specific items not covered in previous published tools. The initial draft was peer-reviewed, experts-views provided, and improved by a scientific committee comprising of field research experts, editorial experts of different journals, and academics working in different organization worldwide. The feedback from continuous online meetings, mail communications, and webinars resulted a final draft in the shape of a checklist tool, covering the best practices related to the field of natural products research in cancer prevention and treatment. It is mandatory for the authors to read and follow the AIMRDA tool, and be aware of the good-practices to be followed in cancer research prior to any submission to APJCP. Though the tool is developed based on experts in the field, it needs to be further updated and validated in practice via implementation in the field.

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.

Background/ Objective: Camel milk is traditionally known for its human health benefits and believed to be a remedy for various human ailments including cancer. The study was aimed to evaluate the inhibitory effects of commercially available camel milk on cancer cells and its underlying mechanism(s). Materials and Methods: Two cell lines: colorectal cancer HCT 116 and breast cancer MCF-7 were cultured with different doses of camel milk. The effects of camel milk on cell death were determined by MTT assay, viability by trypan blue exclusion assay and migration by in vitro scratch assay. The mechanism was elucidated by western blotting and confocal microscopy was used to confirm autophagy. Results: Camel milk significantly reduced proliferation, viability as well as migration of both the cells. The accumulation of LC3-II protein along with reduction in expression of p62 and Atg 5-12, the autophagy proteins implied induction of autophagy. The (GFP)-LC3 puncta detected by confocal microscopy confirmed the autophagosome formation in response to camel milk treatment. Conclusion: Camel milk exerted antiproliferative effects on human colorectal HCT 116 and breast MCF-7 cancer cells by inducing autophagy., (Creative Commons Attribution License)

Sanguinarine (Sang) - a benzophenanthridine alkaloid extracted from Sanguinaria canadensis - exhibits antioxidant, anti-inflammatory, proapoptotic and growth inhibitory activities on tumor cells of various cancer types as established by in vivo and in vitro studies. Although the underlying mechanism of Sang antitumor activity is yet to be fully elucidated, Sang has displayed multiple biological effects, which remain to suggest its possible use in plant-derived treatments of human malignancies. This review covers the anticancer abilities of Sang including inhibition of aberrantly activated signal transduction pathways, induction of cell death and inhibition of cancer cell proliferation. It also highlights Sang-mediated inhibition of angiogenesis, inducing the expression of tumor suppressors, sensitization of cancer cells to standard chemotherapeutics to enhance their cytotoxic effects, while addressing the present need for further pharmacokinetic-based studies.

Context: Papillary thyroid cancer (PTC) is the second most common cancer in females in Saudi Arabia. However, the pathogenesis of PTC is still not fully elucidated., Objective: To identify potential genes that play important role in progression of PTC, we studied the role of X-linked inhibitor of apoptosis protein (XIAP) as a potential prognostic marker and therapeutic target in a large cohort of PTC samples and cell lines., Design: A DNA microarray chip was used to screen for gene copy number. XIAP expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of 1022 clinical samples. In vitro and in vivo studies were performed using Embelin and/or LY294002 on PTC cell lines., Results: XIAP was found to be amplified in 14 of 29 and overexpressed in 48.8% of PTC cases. XIAP overexpression was significantly associated with old age, extrathyroidal extension, tumor size, nodal involvement, tall-cell variant, advanced stage disease, and significantly poor disease-free survival (P = .0341). XIAP was also significantly associated with phosphorylated AKT (P < .0001), Bcl-Xl (P < .0001), and Ki67 (P = .0006) proteins. Embelin treatment caused growth inhibition and apoptosis in PTC cell lines and induced tumor regression in PTC xenograft in nude mice. Finally, the combination of suboptimal doses of Embelin and LY294002 induced a synergistic apoptotic response in PTC cells., Conclusion: XIAP dysregulation in PTC confers an aggressive phenotype with poor outcome. In vitro and in vivo studies using an XIAP inhibitor suggest that this subgroup of PTC with overexpression of XIAP can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in these cancers.

Background: FoxM1 has been shown to play a critical role in the pathogenesis of various epithelial malignancies. However, its role in lymphoid malignancies has not been fully clarified. We, therefore, investigated the role of FoxM1 expression in a large cohort of diffuse large B-cell lymphoma samples and panel of cell lines., Design and Methods: FoxM1 expression was investigated in a large series of diffuse large B-cell lymphoma tissues in a tissue microarray format by immunohistochemistry. Apoptosis was measured by flow cytometry and protein expression was detected by immunoblotting using diffuse large B-cell lymphoma cell lines following treatment with either pharmacological inhibitor of FoxM1 or small interference RNA knockdown strategy. Invasion/migration and soft agar colony assays were also performed following treatment with FoxM1 inhibitor., Results: FoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215). Expression of small interference RNA targeted against FoxM1 or treatment of diffuse large B-cell lymphoma cells with thiostrepton caused its downregulation accompanied by decreased expression of matrix metalloproteinases-2 and matrix metalloproteinases-9. Inhibition of FoxM1 in diffuse large B-cell lymphoma cells also decreased invasive and migratory capability, and induced caspase dependent apoptosis via activation of the mitochondrial apoptotic pathway. Finally, combined thiostrepton and bortezomib at sub-toxic doses led to efficient apoptosis in diffuse large B-cell lymphoma cells., Conclusions: Altogether, these results suggest that FoxM1 is over-expressed in the majority of diffuse large B-cell lymphoma samples. These data also indicate that targeting FoxM1 signaling can serve as a potential therapeutic modality in the management of diffuse large B-cell lymphoma.

Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cyclin-dependent kinase inhibitor p27Kip1 through ubiquitin-mediated degradation. SKP2 is frequently overexpressed in variety of cancers. We investigated the function of SKP2 and its ubiquitin-proteasome pathway in a large series (156) of epithelial ovarian cancer (EOC) patient samples, using a panel of cell lines, and nude mouse model. Using immunohistochemistry, we detected SKP2 in 13.2% tumor samples and found that it was inversely associated with p27Kip1. EOC subset with high level of SKP2 and low level of p27Kip1 showed a strong association with proliferative marker Ki167 (P<0.0014). Treatment of EOC cell lines with bortezomib or expression of siRNA of SKP2 causes downregulation of SKP2 and accumulation of p27Kip1. In addition, co-treatment of EOC with bortezomib and cisplatin causes more pronounced effect on cell proliferation, apoptosis and downregulation of SKP2 leading to accumulation of p27kip1. Bortezomib treatment of EOC cells causes apoptosis by involving mitochondrial pathway, activation of caspases and downregulation of XIAP, and survivin. Finally, treatment of EOC cell line xenografts with bortezomib resulted in growth inhibition of tumors in nude mice through downregulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and ubiquitin-proteasome pathway may be a potential target for therapeutic intervention for treatment of EOC.

Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. MG-132, a proteasome inhibitor, suppresses cell proliferation and induces apoptosis in several PEL cell lines. Treatment of PEL cells with MG-132 results in downregulation of S-phase kinase protein 2 (SKP2) and accumulation of p27Kip1. Furthermore, MG-132 treatment of PEL cells causes Bax conformational changes, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosole. Such cytochrome c release results in sequential activation of caspases and apoptosis, while pretreatment of PEL cells with universal inhibitor of caspases, z-VAD-fmk prevents cell death induced by MG-132. Finally, our data demonstrated in PEL cells that MG-132 downregulates the expression of inhibitor of apoptosis proteins XIAP, cIAP1 and survivin. Altogether, these findings suggest that MG-132 is a potent inducer of apoptosis of PEL cells via downregulation of SKP2 leading to accumulation of p27Kip1, resulting in cell cycle arrest and apoptosis and strongly suggest that targeting the proteasomal pathway may provide a novel therapeutic approach for the treatment of PEL.

Background: Emerging evidence suggests that natural plant ingredients have played an important role in the healthcare of many countries. Several of these natural plant products possess therapeutic potential for various diseases including cancer. Curcumin is the pigment of turmeric, a well-known chemopreventive agent that has been shown to suppress the proliferation of a wide variety of tumor cells, including lymphoma. Curcumin has been shown to have cancer chemopreventive potential against a variety of tumors via targeting key survival pathways that are aberrantly activated in cancer cells., Methods: This review discusses therapeutic potential of curcumin in malignancies of lymphoma as well as therapeutic implications of the recent advances in the field., Results/conclusion: Dietary-compound curcumin hardwires to multiple cellular processes. Suppression of cell proliferation, induction of apoptosis, and inhibition of metastasis are considered to be the major mechanisms underlying its anticancer properties.

We provide evidence that curcumin, a natural compound isolated from rhizomes of plant Curcuma longa, induces apoptosis in several Burkitt's lymphoma cell lines expressing Bax protein (AS283A, KK124, and Pa682PB), whereas it has no effects in cell lines with no Bax expression (BML895 and CA46). Our data show that curcumin treatment results in down-regulation of constitutive activation of nuclear factor-kappaB (NF-kappaB) via generation of reactive oxygen species where it causes conformational changes in Bax protein leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and poly(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, curcumin treatment of Burkitt's lymphoma cell lines also causes up-regulation of DR5; however, this up-regulation does not result in apoptosis. Importantly, cotreatment with curcumin and TRAIL induces apoptosis in Bax-deficient cell lines. Taken together, our findings suggest that curcumin is able to induce apoptosis in Bax-positive cell lines, whereas combinations with TRAIL result in apoptosis in Bax-negative cell lines. These findings also raise the possibility that incorporation of curcumin in treatment regimens may provide a novel approach for the treatment of Burkitt's lymphomas and provide the molecular basis for such future translational efforts.

The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1). Our data also demonstrate that curcumin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for curcumin, acting as a suppressor of JAK-1 and STAT3 activation in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. Therefore, curcumin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of STAT3.

The growing global burden of malignant tumors with increasing incidence and mortality rates underscores the urgent need for more effective and less toxic therapeutic options. Herbal compounds are being increasingly studied for their potential to meet these needs due to their reduced side effects and significant efficacy. Pristimerin (PS), a triterpenoid from the quinone formamide class derived from the Celastraceae and Hippocrateaceae families, has emerged as a potent anticancer agent. It exhibits broad-spectrum anti-tumor activity across various cancers such as breast, pancreatic, prostate, glioblastoma, colorectal, cervical, and lung cancers. PS modulates several key cellular processes, including apoptosis, autophagy, cell migration and invasion, angiogenesis, and resistance to chemotherapy, targeting crucial signaling pathways such as those involving NF-κB, p53, and STAT3, among others. The main objective of this review is to provide a comprehensive synthesis of the current literature on PS, emphasizing its mechanisms of action and molecular targets with the utmost clarity. It discusses the comparative advantages of PS over current cancer therapies and explores the implications for future research and clinical applications. By delineating the specific pathways and targets affected by PS, this review seeks to offer valuable insights and directions for future research in this field. The information gathered in this review could pave the way for the successful development of PS into a clinically applicable anticancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Gynecological cancers are among the most commonly diagnosed cancers in women globally. Despite advancements in diagnostics and treatments, these cancers remain a significant health problem. Alternative medicines, such as isothiocyanates (ITCs), have gained attention for their potential effectiveness against various types of cancers. ITCs, including sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate have demonstrated considerable ability to inhibit cancer cell growth, induce cell death, and modulate other cellular processes in female-specific cancers. Moreover, ITCs may enhance the chemo-sensitization of chemotherapeutic drugs, improving efficacy in combination with conventional treatments or other phytochemicals. Studies suggest that ITCs may be effective either as standalone treatments or in combination with conventional chemotherapies for the prevention or treatment of female-specific cancers. Improved understanding of the molecular intricacies of ITCs could lead to better treatment options for these cancers. Seemingly, a better understanding of these molecular aspects could open new horizons for ITC-based therapeutic interventions, potentially improving the prognosis of female-specific cancer patients. Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the years, alternative and complementary medicine have garnered much attention all across the globe. To this end, phytochemicals have intriguing potential against myriads of disease conditions; nevertheless, as of yet, the molecular intricacies for their therapeutic potential is incompletely understood. It is widely acknowledged that proteomics technology has been ex-plored as a reliable approach to understand the molecular intricacies related to phytochemi-cal-based therapeutic interventions. Reckoning with this, the present review provides an overview of the proteomics studies performed to unravel the underlying molecular intricacies of various phytochemicals such as Curcumin, Genistein, and Tanshinone IIA. Phytochemicals possess various intriguing pharmacological properties against diverse pathological conditions. Extensive studies are on-going to understand the structural/functional properties of phytochemicals as well as the molecular mechanisms of their therapeutic function against various disease conditions. Phytochemicals such as curcumin (Cur), genistein (Gen), and tanshinone-IIA (Tan IIA) have multifaceted therapeutic potentials and various efforts are in progress to understand the molecular dynamics of their function with different tools and technologies. Cur is an active lipophilic polyphenol with pleiotropic function, and it has been shown to possess various intriguing properties including antioxidant, anti-inflammatory, anti-microbial, anticancer, and anti-genotoxic properties besides others beneficial properties. Similarly, Gen (an isoflavone) exhibits a wide range of vital functions including antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-angiogenic activities etc. In addition, Tan IIA, a lipophilic compound, possesses antioxidant, anti-angiogenic, anti-inflammatory, anticancer activities, and so on. Over the last few decades, the field of proteomics has garnered great momentum mainly attributed to the recent advancement in mass spectrometry (MS) techniques. It is envisaged that the proteomics technology has considerably contributed to the biomedical research endeavors lately. Interestingly, they have also been explored as a reliable approach to understand the molecular intricacies related to phytochemical-based therapeutic interventions. The present review provides an overview of the proteomics studies performed to unravel the underlying molecular intricacies of various phytochemicals such as Cur, Gen, and Tan IIA. This in-depth study will help the researchers in better understanding of the pharmacological potential of the phytochemicals at the proteomics level. Certainly, this review will be highly instrumental in catalyzing the translational shift from phytochemical-based biomedical research to clinical practice in the near future. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a cancer of white blood cells known as plasma cells. It is hard to treat cancer, thus requires new treatments. Herein, a plant extracted compound, guggulsterone (GS), has been investigated for its anticancer activity in MM cells. The results from this study revealed that GS could be used for the effective treatment of MM due to its ability to cause cell death in MM cells. It exhibits anticancer activity itself and also increases the effectiveness of other drugs when combined. Therefore, it could be further investigated for its possible utilization in clinics to treat MM patients. Multiple myeloma (MM) is a hematological disorder characterized by the abnormal expansion of plasma cells in the bone marrow. Despite great advances over the past three decades in discovering the efficacious therapies for MM, the disease remains incurable for most patients owing to emergence of drug-resistant cancerous cells. Guggulsterone (GS), a phytosteroid, extracted from the gum resin of guggul plant, has displayed various anticancer activities in vitro and in vivo; however, the molecular mechanisms of its anticancer activity have not been evaluated in MM cells. Therefore, in this study, we investigated the anticancer activity of GS in various MM cell lines (U266, MM.1S, and RPMI 8226) and the mechanisms involved. GS treatment of MM cells caused inhibition of cell proliferation and induction of apoptotic cell death as indicated by increased Bax protein expression, activation of caspases, and cleavage of poly (ADP-ribose) polymerase. This was associated with the downregulation of various proliferative and antiapoptotic gene products, including cyclin D, Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. GS also suppressed the constitutive and interleukin 6-induced activation of STAT3. Interestingly, the inhibition of Janus activated kinase or STAT3 activity by the specific inhibitors or by siRNA knockdown of STAT3 resulted in the downregulation of HMGB1, suggesting an association between GS, STAT3, and HMGB1. Finally, GS potentiated the anticancer effects of bortezomib (BTZ) in MM cells. Herein, we demonstrated that GS could be a potential therapeutic agent for the treatment of MM, possibly alone or in combination with BTZ. [ABSTRACT FROM AUTHOR]

Curcumae Rhizoma, also known as Ezhu is a traditional Chinese medicine that has been used for many centuries against several diseases. The rhizome of the plant is composed of curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), and essential volatile oils including curcumol, curdione, and germacrone. While curcuminoids have been extensively studied for their antimicrobial, antioxidant, anti-inflammatory and anticancer properties, the therapeutic efficacy of curcumol is still emerging. Recent studies have shown anticancer properties of curcumol against multiple solid tumors such as breast, colorectal, head and neck, and lung adenocarcinomas. The underlying anti-tumor mechanisms revealed inhibition of several signaling pathways (NF-κB, MAPK, PI-3K/AKT, and GSK-3β) associated with cell proliferation, survival, anti-apoptosis, invasion and metastasis. Besides curcumol, extracts from the Curcumae Rhizoma roots possess many other terpenoids such as β-elemene, δ-elemene, germacrone, furanodiene and furanodienone with known anticancer properties. In this review, we comprehensively focused on the composition of Curcumae Rhizoma essential oils, their structure, isolation and therapeutic uses of curcumol to aid in the improvement and development of novel drugs with minimal cytotoxicity, enhanced efficacy, and less cost. [ABSTRACT FROM AUTHOR]

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM. [ABSTRACT FROM AUTHOR]

Background: Proteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade(®), a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML.Methods: Cell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose.Results: Treatment of CML cells with bortezomib results in downregulation of S-phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells.Conclusions: Altogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML. [ABSTRACT FROM AUTHOR]

Background: Cross-talk between deregulated signaling pathways in cancer cells causes uncontrolled growth and proliferation. These cancers cells become more aggressive and quickly develop resistance to therapy. Therefore targeting of these deregulated pathways simultaneously can result in efficient cell death of cancer cells. In this study we investigated co-expression of Cox-2 and FoxM1 in a cohort of colorectal carcinoma (CRC) samples and also examined whether inhibition of Cox-2 and FoxM1 simultaneously can lead to inhibition of cell viability and induction of apoptosis in colorectal cancer cell lines and in vivo xenografts. Methods: Protein expression of Cox-2 and FoxM1 was determined in a large cohort of 770 clinical CRC samples in a tissue micro-array format by immunohistochemistry. Cell death was measured using live dead assay. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Calcusyn software was utilized to estimate the synergistic doses using chou and Talalay method. Results: Co-expression of Cox-2 and FoxM1 was detected in 33.3 % (232/697) of CRC's and associated with an aggressive phenotype characterized by younger age (p = 0.0191), high proliferative index marker; Ki-67 (p = 0.004) and MMP-9 (p = 0.0116) as well as activation of AKT (p = 0.0214). In vitro, inhibition of FoxM1 and Cox-2 with pharmacological inhibitors; Thiostrepton and NS398 resulted in efficient down-regulation of FoxM1 and Cox-2 expression along with in-activation of AKT and inhibition of colony formation, invasion and migratory capability of CRC cells. In addition, there was also inhibition of cell viability and induction of apoptosis via the mitochondrial apoptotic pathway in CRC cell lines. Finally, treatment of CRC xenograft tumors in nude mice with combination of Cox-2 and FoxM1 inhibitors inhibited tumor growth significantly via down-regulation of Cox-2 and FoxM1 expression. Conclusions: These findings demonstrate that co-expression of Cox-2 and FoxM1 might play a critical role in the pathogenesis of CRC. Therefore, targeting of these pathways simultaneously with sub toxic doses of pharmacological inhibitors can be a potential therapeutic approach for the treatment of this subset of CRC. [ABSTRACT FROM AUTHOR]

Activated B-cell lymphoma (ABC), one of the three subtypes of Diffuse Large B-cell Lymphoma (DLBCL) has the worst survival rate after upfront chemotherapy and is characterized by constitutively activated NFκB. We therefore studied the role of NFκB In a cohort of clinical DLBCL samples and ABC cell lines. In our clinical tissue microarray cohort of DLBCL samples, p-IκBα was detected in 38.3% of ABC DLBCL and was an independent prognostic marker for poor survival. In vitro, we found that Thymoquinone (TQ), a natural compound isolated from Nigella sativa caused release of ROS in ABC cells. TQ-mediated release of ROS in turn inhibited NFκB activity by dephosphorylating IκBα and decreased translocation of p65 subunit of NFκB in the nuclear compartment in ABC cell lines. This led to inhibition of cell viability and induction of mitochondrial dependent apoptosis in ABC-DLBCL cell lines. Additionally, TQ treatment also caused up-regulation of death receptor 5 (DR5), however, up-regulation of DR5 did not play a role in TQ-induced apoptosis. Finally, combination of sub-optimal doses of TQ and TRAIL induced efficient apoptosis in ABC-DLBCL cell lines. These data show that p-IκBα can be used as a prognostic marker and target for therapy in this aggressive sub-type of DLBCL and TQ may play an important role in the management of DLBCL in the future. [ABSTRACT FROM AUTHOR]

Neosetophomone B (NSP–B), a meroterpenoid fungal secondary metabolite, was investigated for its anticancer potential in leukemic cell lines (K562 and U937). NSP-B treatment of leukemic cells suppressed cell viability by triggering apoptotic cell death. Apoptosis induced by NSP-B is triggered by mitochondrial signaling and caspase activation. Additionally, NSP-B treatment of leukemic cells causes AKT's inactivation accompanied by downregulation of SKP2 oncogene and MTH1 with a concomitant increase of p21Cip1and p27Kip1. Furthermore, NSP-B causes suppression of antiapoptotic proteins, including cIAP1, cIAP2, XIAP, survivin and BCl-XL. Overall, NSP-B reduces cell viability by mitochondrial and caspase-dependent apoptosis. The inhibition of AKT and SKP2 axis could be a promising therapeutic target for leukemia treatment. • Anticancer activity of NSP-B, a secondary fungal metabolite isolated from Neosetophoma sp, has not been explored in any cancer so far. • AKT/SKP2 signaling pathway is frequently deregulated in human cancers, including leukemia. • NSP-B inhibited activation of AKT/SKP2 in leukemic cells. • NSP-B suppressed cell proliferation and inhibited apoptosis via activation of mitochondrial and caspase signaling in leukemic cells. • NSP-B could be a novel anticancer drug for the treatment of leukemia and other hematological malignancies. [ABSTRACT FROM AUTHOR]

• Resorcylic acid lactones (RALs) are fungal polyketides. • RALs consist of a β-resorcylic acid residue embedded in a macrolactone ring. • RALs exhibit a broad range of biological activities, including anticancer activities. • Radicicol, a RAL, selectively inhibits Hsp90. • Several RALs inhibit protein kinases and nuclear factor kappa B (NF-κB). Resorcylic acid lactones (RALs) are fungal polyketides that consist of a β-resorcylic acid residue (2,4-dihydroxybenzoic acid) embedded in a macrolactone ring. RALs exhibit a broad range of biological activities, including anticancer activities. Following discovery of the selective Hsp90 inhibition activity of radicicol, the kinase inhibition activity of hypothemycin, monocillin II, 5Z-7-oxo-zeaenol, and L-783,277 RALs, and the nuclear factor kappa B (NF-κB) inhibition activity of the RAL zearalenone, have attracted great attention as potential therapeutics for cancer treatment. In this minireview, we focus on natural RALs that possess cytotoxic activities [IC 50 values < 10 μM (or 4–5 μg/ml)], discussing their structures, isolation, occurrence, biological activities, and anticancer molecular mechanisms. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma is a frequent skin cancer still demanding to understand the underlying mechanisms for better clinical outcomes. Pristimerin, a natural quinonemethide triterpenoid , has shown promising therapeutic outcome due to its anti-cancer activity and multi-targeting potential. We explored the underlying mechanisms of pristimerin-induced programmed cell death of primary (A431) and metastatic (A388) cutaneous squamous cell carcinoma (cSCC) cells. Our results show that pristimerin inhibits growth and proliferation of cSCC through JNK activation. Moreover, pristimerin causes cell cycle arrest and induces cell death via apoptosis and autophagy. Interestingly, use of apoptosis (z-VAD-FMK) and autophagy (3-methyladenine) inhibitors confirmed vital role of programmed cell death in pristimerin-mediated anti-cancer actions. JNK inhibitor, SP600125, also mitigated pristimerin-induced apoptotic and autophagic actions. Moreover, pristimerin-mediated anti-cancer activity acts by generating reactive oxygen species (ROS) thereby inducing JNK signaling. Use of N-acetyl cystine (NAC), a universal ROS scavenger, significantly reversed pristimerin-induced programmed cell death through downregulation of JNK. Pristimerin sensitized skin cancer cells to conventional anticancer drugs cisplatin, azacytidine and doxorubicin through JNK activation, as confirmed by SP600125. Our results indicate that pristimerin mediates programmed cell death and sensitized skin cancer cells to conventional anti-cancer drugs via ROS-mediated JNK activation. [Display omitted] • Skin cancer is one of the most common human cancer with increasing challenges. • Pristimerin has shown promising therapeutic outcome due its multi-targeting potential. • Pristimerin induces programmed cell death via ROS-mediated JNK activation. • Pristimerin sensitized skin cancer cells to conventional anti-cancer drugs. • Pristimerin attenuated stemness markers in skin cancer cells. [ABSTRACT FROM AUTHOR]

Objective: The mechanisms by which interferon α (IFN-α) induces antileukemic responses in chronic myelogenous leukemia (CML) cells are not known. We examined whether a member of the protein kinase C (PKC) family of proteins, PKC-δ, is activated during treatment of BCR-ABL cells with IFN-α and participates in the induction of interferon responses. Methods: Immunoblots and immune complex kinase assays were performed to study the phosphorylation and activation of PKC-δ in response to IFN-α in CML-derived cell lines. The effects of pharmacological inhibition of PKC-δ on the suppressive effects of IFN-α on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose. Results: IFN-α treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-δ and activation of its kinase domain. Such phosphorylation/activation of PKC-δ was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-δ activity blocked the IFN-α–dependent serine phosphorylation of Stat1 and IFN-α–inducible gene transcription. IFN-α treatment strongly inhibited leukemic CFU-GM progenitor colony fromation from bone marrow or peripheral blood of patients with CML, and such inhibition was reversed by concomitant treatment of the cells with the PKC-δ pharmacologic inhibitor rottlerin. Conclusion: Taken altogether, our data demonstrate that PKC-δ plays a critical role in Type I IFN signaling in BCR-ABL expressing cells, acting as a serine kinase for Stat1, to regulate transcriptional activation of interferon-regulated genes and induction of antileukemic responses. [Copyright &y& Elsevier]