Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells

Betulin and betulinic acid are naturally occurring pentacyclic triterpenes showing cytotoxicity towards a number of cancer cell lines. Unfortunately they are practically insoluble in aqueous media and therefore their overall absorption index is not satisfactory. We have modified structures of both compounds by simple transformation to mono- and disubstituted esters of l-amino acids. This allowed us to achieve better water solubility without loss of the observed earlier anticancer properties. Comet assay on various cancer cell lines demonstrate that these compounds act via an apoptotic mechanism.     

The tyrosine kinase v-Src modifies cytotoxicities of anticancer drugs targeting cell division

v-Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v-Src-mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities-mediated chromosome instability. v-Src directly phosphorylates Tyr-15 of cyclin-dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v-Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v-Src restores cancer cell viability reduced by various microtubule-targeting agents (MTAs), although v-Src does not alter cytotoxicity of DNA-damaging anticancer drugs. v-Src causes mitotic slippage of MTAs-treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v-Src also restores cell viability reduced by a polo-like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v-Src. These results suggest that the v-Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src-induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs.     

Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1

In this study, a peptide–peptide co-administration therapy between hybrid peptide kla-TAT and cationic anticancer peptide HPRP-A1 was designed to increase the anticancer activity of the combination peptides through synergistic effect. kla is a pro-apoptotic peptide which could induce rapid cancer cell apoptosis by disruption the mitochondrial membrane when internalized the cells. To enhance more kla peptides pass through cell membrane, a double improvement strategy was designed by chemically conjugation with cell penetration peptide TAT as well as co-administration with cationic membrane active peptide HPRP-A1, and the double anticancer mechanism of the kla-TAT peptide and HPRP-A1 including membrane disruption and apoptosis induction was verified through in vitro experiments. The CompuSyn synergism/antagonism analysis showed that kla-TAT acted synergistically with HPRP-A1 against a non-small cell lung cancer (NSCLC) A549 cell line. The anticancer activities of the two peptides were dramatically increased by co-administration, under the mechanism of cell membrane disruption, caspase-dependent apoptosis induction, as well as cyclin-D1 down-regulation based G1 phase arrest. We believe that the synergic therapeutic strategy would be a meaningful method for the anticancer peptides used in cancer treatment.     

Strong electronic charge as an important factor for anticancer activity of chitooligosaccharides (COS)

Even though several studies report the importance of chitosan derivatives for their anticancer activity, no clear information is available to describe the relationship between their charge properties and observed activities. In this research, differently charged chitooligosaccharide (COS) derivatives were synthesized and their anticancer activities were studied using three cancer cell lines, HeLa, Hep3B and SW480. Neutral red and MTT cell viability studies revealed that, highly charged COS derivatives could significantly reduce cancer cell viability, regardless to the positive or negative charge. Further, fluorescence microscopic observations and DNA fragmentation studies confirmed that the anticancer effect of these highly charged COS derivatives were due to necrosis. However, the exact molecular mechanism for anticancer activity of strongly charged COS compared to their poorly charged counterparts is not clear.     

Caspase-driven cancer therapies: Navigating the bridge between lab discoveries and clinical applications

Apoptosis is the cell's natural intrinsic regulatory mechanism of normal cells for programmed cell death, which plays an important role in cancer as a classical mechanism of tumor cell death causing minimal inflammation without causing damage to other cells in the vicinity. Induction of apoptosis by activation of caspases is one of the primary targets for cancer treatment. Over the years, a diverse range of natural, synthetic, and semisynthetic compounds and their derivatives have been investigated for their caspase-mediated apoptosis-induced anticancer activities. The review aims to compile the preclinical evidence and highlight the critical mechanistic pathways related to caspase-induced cell apoptosis in cancer treatment. The focus is placed on the key components of the mechanisms, including their chemical nature, and specific attention is given to phytochemicals derived from natural sources and synthetic and semisynthetic compounds. 180+ compounds from the past two decades with potential as anticancer agents are discussed in this review article. By summarizing the current knowledge and advancements in this field, this review provides a comprehensive overview of potential therapeutic strategies targeting apoptosis in cancer cells. The findings presented herein contribute to the ongoing efforts to combat cancer and stimulate further research into the development of effective and targeted anticancer therapies.     

Cell penetrating peptide TAT can kill cancer cells via membrane disruption after attachment of camptothecin

Attachment of traditional anticancer drugs to cell penetrating peptides is an effective strategy to improve their application in cancer treatment. In this study, we designed and synthesized the conjugates TAT-CPT and TAT-2CPT by attaching camptothecin (CPT) to the N-terminus of the cell penetrating peptide TAT. Interestingly, we found that TAT-CPT and especially TAT-2CPT could kill cancer cells via membrane disruption, which is similar to antimicrobial peptides. This might be because that CPT could perform as a hydrophobic residue to increase the extent of membrane insertion of TAT and the stability of the pores. In addition, TAT-CPT and TAT-2CPT could also kill cancer cells by the released CPT after they entered cells. Taken together, attachment of CPT could turn cell penetrating peptide TAT into an antimicrobial peptide with a dual mechanism of anticancer action, which presents a new strategy to develop anticancer peptides based on cell penetrating peptides.     

Polyether ionophores—promising bioactive molecules for cancer therapy

The natural polyether ionophore antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the polyether ionophores undergoing pre-clinical evaluation are reviewed. Most of polyether ionophores have shown potent activity against the proliferation of various cancer cells, including those that display multidrug resistance (MDR) and cancer stem cells (CSC). The mechanism underlying the anticancer activity of ionophore agents can be related to their ability to form complexes with metal cations and transport them across cellular and subcellular membranes. Increasing evidence shows that the anticancer activity of polyether ionophores may be a consequence of the induction of apoptosis leading to apoptotic cell death, arresting cell cycle progression, induction of the cell oxidative stress, loss of mitochondrial membrane potential, reversion of MDR, synergistic anticancer effect with other anticancer drugs, etc. Continued investigation of the mechanisms of action and development of new polyether ionophores and their derivatives may provide more effective therapeutic drugs for cancer treatments.     

New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis

A series of novel bichalcone analogs were synthesized and evaluated in lipopolysaccharide (LPS)-activated microglial cells as inhibitors of nitric oxide (NO) and for in vitro anticancer activity using a limited panel of four human cancer cell lines. All analogs inhibited NO production. Compounds 4 and 11 exhibited optimal activity with IC(50) values of 0.3 and 0.5 μM, respectively, and were at least 38-fold better than the positive control. A mechanism of action study showed that both compounds significantly blocked the nuclear translocation of NF-κB p65 and up-regulation of iNOS at 1.0 μM. Compound 4 and three other analogs (3, 20, and 23) exerted significant in vitro anticancer activity GI(50) values ranging from 0.70 to 13.10 μM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling.     

Acquisition of resistance of pancreatic cancer cells to 2-methoxyestradiol is associated with the upregulation of manganese superoxide dismutase

Acquired resistance of cancer cells to anticancer drugs or ionizing radiation (IR) is one of the major obstacles in cancer treatment. Pancreatic cancer is an exceptional aggressive cancer, and acquired drug resistance in this cancer is common. Reactive oxygen species (ROS) play an essential role in cell apoptosis, which is a key mechanism by which radio- or chemotherapy induce cell killing. Mitochondria are the major source of ROS in cells. Thus, alterations in the expression of mitochondrial proteins, involved in ROS production or scavenging, may be closely linked to the resistance of cancer cells to radio- or chemotherapy. In the present study, we generated a stable cell line by exposing pancreatic cancer cells to increasing concentrations of ROS-inducing, anticancer compound 2-methoxyestradiol (2-ME) over a 3-month period. The resulting cell line showed strong resistance to 2-ME and contained an elevated level of ROS. We then used a comparative proteomics method to profile the differential expression of mitochondrial proteins between the parental and the resistant cells. One protein identified to be upregulated in the resistant cells was manganese superoxide dismutase (SOD2), a mitochondrial protein that converts superoxide radicals to hydrogen peroxides. Silencing of SOD2 resensitized the resistant cells to 2-ME, and overexpression of SOD2 led the parental cells to 2-ME resistance. In addition, the 2-ME-resistant cells also showed resistance to IR. Our results suggest that upregulation of SOD2 expression is an important mechanism by which pancreatic cancer cells acquire resistance to ROS-inducing, anticancer drugs, and potentially also to IR.     

Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.     

JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs

Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.     

Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation

Chemotherapy has been widely used as a clinical treatment for cancer over the years. However, its effectiveness is limited because of resistance of cancer cells to programmed cell death (PCD) after treatment with anticancer drugs. To elucidate the resistance mechanism, we initially focused on cancer cell-specific mitophagy, an autophagic degradation of damaged mitochondria. This is because mitophagy has been reported to provide cancer cells with high resistance to anticancer drugs. Our data showed that TRIP-Br1 oncoprotein level was greatly increased in the mitochondria of breast cancer cells after treatment with various anticancer drugs including staurosporine (STS), the main focus of this study. STS treatment increased cellular ROS generation in cancer cells, which triggered mitochondrial translocation of TRIP-Br1 from the cytosol via dephosphorylation of TRIP-Br1 by protein phosphatase 2A (PP2A). Up-regulated mitochondrial TRIP-Br1 suppressed cellular ROS levels. In addition, TRIP-Br1 rapidly removed STS-mediated damaged mitochondria by activating mitophagy. It eventually suppressed STS-mediated PCD via degradation of VDACI, TOMM20, and TIMM23 mitochondrial membrane proteins. TRIP-Br1 enhanced mitophagy by increasing expression levels of two crucial lysosomal proteases, cathepsins B and D. In conclusion, TRIP-Br1 can suppress the sensitivity of breast cancer cells to anticancer drugs by activating autophagy/mitophagy, eventually promoting cancer cell survival.     

Synthesis of pheophorbide-a conjugates with anticancer drugs as potential cancer diagnostic and therapeutic agents

Pheophorbide-a, a chlorine based photosensitizer known to be selectively accumulated in cancer cells, was conjugated with anticancer drugs, doxorubicin and paclitaxel in the purpose of selective cancer diagnosis and therapy. Pheophorbide-a was conjugated with anticancer drugs via directly and by the use of selective cleavage linkers in cancer cell. The fluorescence of pheophorbide-a and doxorubicin conjugate by excitation at 420 or 440 nm was greatly diminished possibly by the energy transfer mechanism between two fluorescent groups. However, upon treatment in cancer cells, the conjugate showed to be cleaved to restore each fluorescence of pheophorbide-a and doxorubicin after 48 h of incubation. Also, pheophorbide-a conjugates either with doxorubicin and paclitaxel inhibited the growth of various cancer cells more potently than pheophorbide-a, which displayed very weak inhibitory activity. The results indicated that the pheophorbide-a conjugates with anticancer drugs could be utilized for selective cancer therapy as well as for the fluorescence detection of cancer.     

Interplay between apoptosis and autophagy,a challenging puzzle: New perspectives on antitumor chemotherapies

Autophagy is a mechanism of protection against various forms of human diseases, such as cancer, in which autophagy seems to have an extremely complex role. In cancer, there is evidence that autophagy may be oncogenic in some contexts, whereas in others it clearly contributes to tumor suppression. In addition, studies have demonstrated the existence of a complex relationship between autophagy and cell death, determining whether a cell will live or die in response to anticancer therapies. Nevertheless, we still need to complete the autophagy–apoptosis puzzle in the tumor context to better address appropriate chemotherapy protocols with autophagy modulators. Generally, tumor cell resistance to anticancer induced-apoptosis can be overcome by autophagy inhibition. However, when an extensive autophagic stimulus is activated, autophagic cell death is observed. In this review, we discuss some details of autophagy and its relationship with tumor progression or suppression, as well as role of autophagy–apoptosis in cancer treatments.     

Heterogeneity of anticancer drug sensitivity in squamous cell carcinoma of the tongue

Heterogeneity is known to be present to varying degrees in cancer cell groups. There have been no reports, however, of studies in which a single cell clone was prepared from a cancer cell group to examine heterogeneity with respect to anticancer drug sensitivity. Thus, the authors herein report an investigation into the heterogeneity of cancer cells within the same tumor with respect to anticancer drug sensitivity. Anticancer drug sensitivity was investigated in primary tumors, metastatic lymph node tumors, recurrent tumors and established cell lines obtained from four cases of tongue cancer using an oxygen electrode apparatus. As differences were observed in anticancer drug sensitivity from one case to another, even though all four were of the same pathological tissue type, the individual differences were apparently significant. Moreover, primary tumors and recurrent tumors demonstrated different sensitivities to the anticancer drugs even in the same patient. When single cell clones were prepared from primary tumors and anticancer drug sensitivity testing was carried out, sensitivity to anticancer drugs that was not seen in the primary tumors was observed. We performed RT-PCR on cell groups derived from this single cell using MDR1, MRP1, MRP2 and ERCC1, which are primary genes that are resistant to anticancer drugs. Expression of MDR and ERCC1 was not observed in single cell clones nos. 1-10. MRP1 and MRP2, on the other hand, were expressed in all of these single cell clones. Because cells with different sensitivity levels were initially present in the cancer cell groups, even when large numbers of cancer cells died in response to anticancer drug therapy, the results suggest the possibility that recurrence and metastasis occur based on cells with differing sensitivities. After examining anticancer drug sensitivity at the single cell level, we believe that anticancer drug-resistant genes may be involved in the heterogeneity of anticancer drug sensitivity with respect to cancer cell groups.     

What if cell culture media do not mimic in vivo redox settings?

Here, I address the topic of suitability for redox research of common settings in cell cultures. This is done through the prism of in vitro anticancer effects of vitamin C. Cell culture media show lower concentrations of iron and a higher level of oxygen compared to interstitial fluid. Such a setup promotes ascorbate-mediated production and accumulation of hydrogen peroxide, which efficiently kills a variety of cancer cell lines. However, the anticancer effects are annihilated if the iron level is corrected to mimic in vivo concentrations. It appears that the potential benefits of application of vitamin C in cancer treatment have been significantly overestimated. This might be true for other pro-oxidative agents as well, such as some (poly)phenols. We urgently need to establish medium formula and culture maintenance settings that are optimal for redox research.     

Recent progress in polyamine research

Polyamines are recognized as cell growth factors in relation to cell proliferation, differentiation, regeneration and malignant transformation. Polyamines play an important role in the growth of normal cells like vascular endothelial cells and also exert various effects on the proliferation and metastasis of malignant cells. The recent studies on the biosynthesis have clearly elucidated its mechanism at the gane levels, which reflects to the development of the inhibitors of the polyamine biosynthesis. One of the main purposes of the studies on the various polyamine synthesis inhibitors is for the development of new anti-cancer agents, based on the characteristics of the polyamine functions. The clinical effects of several inhibitors, however, have not been shown to be satisfactory and the reason is now the most important research subject in this field. The measurement of the polyamine contents in biological fluids including urine and blood has been shown to be useful as the tumor marker. The recent studies have indicated that the mechanism of increased secretion of urinary polyamines is due to the release from the degraded cancer cells. The results now stimulated the research which aims to elucidate the usefulness of the measurement of urinary polyamines as the parameters of the sensitivity to the anticancer drugs in patients with cancer.     

Induction of cell senescence by targeting to Cullin-RING Ligases (CRLs) for effective cancer therapy

Cullin-RING ligases (CRLs) are the biggest family of multiunit ubiquitin E3 ligases, controlling many biological processes by promoting the degradation of a broad spectrum of proteins associated with cell cycle, signal transduction and cell growth. The dysfunction of CRLs causes a lot of diseases including cancer, which meanwhile offers us a promising approach to cancer therapy by targeting to CRLs. Recent studies have demonstrated that genetic or pharmaceutical inactivation of CRLs often leads to cancer cell death by activating multiple cell-killing pathways including senescence, an emerging anticancer mechanism of therapeutic agents. Here, we summarize the induction of cellular senescence and its mechanism of action, triggered by targeting to specific subunits of CRLs via multiple approaches including siRNA silencing, genetic knockout as well as small molecule inhibitor, exhibiting anticancer effect in vitro and in vivo.     

The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers

Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and ovarian cancer, etc. The related molecular mechanisms corresponding to the anticancer activities of emodin are involved in the induction of apoptosis, inhibition of cell proliferation, enhanced reactive oxygen species (ROS) accumulation, and induction of autophagy, etc. In the present review, we summarized the sources, anticancer properties in vitro and in vivo, molecular mechanisms, metabolic transformation and toxicities of emodin. In addition, we also discussed the limitations of the present investigations of emodin against cancers and gave some perspectives for them, which would be beneficial for the further exploration and development of this natural compound as a clinical cancer drug.