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Twenty-six eudesmanolides including six undescribed compounds were isolated from the flowers of Sphagneticola trilobata (L.) Pruski. Their structures were elucidated based on the interpretation of spectroscopic techniques, NMR calculation, and DP4+ analysis. The stereochemistry of (1S,4S,5R,6S,7R,8S,9R,10S,11S)-1,4,8- trihydroxy-6-isobutyryloxy-11-methyleudesman-9,12-olide (1) was demonstrated by single crystal X-ray diffraction. All eudesmanolides were evaluated for their anti-proliferative activities against four human tumor cell lines (HepG2, HeLa, SGC-7901, and MCF-7). 1α,4β-Dihydroxy-6α-methacryloxy-8β-isobutyryloxyeudesman-9,12-olide (3) and wedelolide B (8) showed pronounced cytotoxic effects against AGS cell line with IC 50 values of 1.31 and 0.89 μM, respectively. Their anti-proliferative activities against AGS cells were exerted through a dose-dependent apoptosis pathway, as verified by cell and nucleus morphological assessment, clone formation assay, and Western blot analysis. Furthermore, 1α,4β,8β-trihydroxy-6β-methacryloxyeudesman-9,12-olide (2) and 1α,4β,9β-trihydroxy-6α-isobutyryloxy- 11α-13-methacryloxyprostatolide (7) performed significant inhibitory effects on lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 macrophages with IC 50 values of 11.82 and 11.05 μM, respectively. Moreover, compounds 2 and 7 could block the nuclear translocation of NF-κB and reduce the expression of iNOS, COX-2, IL-1β, and IL-6 to exert anti-inflammatory effects. This study provides evidence for the utilization of the eudesmanolides from S. trilobata as lead compounds for further research due to their cytotoxic potential., 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 Elsevier Ltd. All rights reserved.)

Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There has been increasing recognition of autophagy as a critical factor affecting tumor cell death and tumor chemoresistance. In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic.

Ethnopharmacological Relevance: Tupistra chinensis Baker (syn. Rohdea chinensis), an antitumor folk herb mainly distributed in China, its rhizome has been historically used to treat gastric cancer. Studies showed that the steroidal saponins were the main bioactive components in the rhizome of T. chinensis. Our previous studies have confirmed that the steroidal saponins have a variety of anti-tumor activities. However, the underlying anti-tumor mechanism of the total steroidal saponins of T. chinensis (TCS) remains to be revealed., Aim of the Study: In the present study, we studied the potential anti-proliferative activity and anti-tumor mechanism of TCS on gastric cancer in vitro and in vivo., Methods: In vitro, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to detect the proliferation ability of TCS on SGC-7901 cells and AGS cells. Flow cytometry were performed to analyze cell apoptosis, cell cycle, mitochondrial membrane potential and reactive oxygen species expression level. Western blotting was performed to validate the expression of proteins in related pathways. In vivo, a xenograft model was established by injecting SGC-7901 cells into nude mice., Results: In vitro, TCS inhibited the proliferation of gastric cancer cells. TCS effectively induced apoptosis by PI3K/Akt/mTOR signaling pathway in SGC-7901 cells, and promoted apoptosis via p53-mediated pathway in AGS cells. TCS also exhibited inhibitory activity in blocking the migration of gastric cancer cells. In vivo, TCS significantly inhibited the growth of xenograft tumor., Conclusion: These results indicated that TCS exhibited significant anti-gastric cancer effects in vitro and in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The efficacy of ongoing anticancer treatment is often compromised by some barriers, such as low drug content, nonspecific release of drug delivery system, and multidrug resistance (MDR) effect of tumors. Herein, in the research a novel functionalized PEG-based polymer cystine-(polyethylene glycol)2-b-(poly(2-methacryloyloxyethyl ferrocenecarboxylate)2) (Cys-(PEG45)2-b-(PMAOEFC)2) with multi-stimuli sensitive mechanism was constructed, in which doxorubicin (DOX) was chemical bonded through Schiff base structure to provide acid labile DOX prodrug (DOX)2-Cys-(PEG45)2-b-(PMAOEFC)2. Afterwards, paclitaxel (PTX) and its diselenide bond linked PTX dimer were encapsulated into the prodrug through physical loading, to achieve pH and triple redox responsive (DOX)2-Cys-(PEG45)2-b-(PMAOEFC)2@PTX and (DOX)2-Cys-(PEG45)2-b-(PMAOEFC)2@PTX dimer with ultrahigh drugs content. The obtained nanovehicles could self-assemble into globular micelles with good stability based on fluorescence spectra and TEM observation. Moreover, there was a remarkable "reassembly-disassembly" behavior caused by phase transition of micelles under the mimic cancerous physiological environment. DOX and PTX could be on-demand released in acid and redox stress mode, respectively. Meanwhile, in vivo anticancer studies revealed the significant tumor inhibition of nanoformulas. This work offered facile strategies to fabricate drug nanaovehicles with tunable drug content and types, it has a profound significance in overcoming MDR effect, which provided more options for sustainable cancer treatment according to the desired drug dosage and the stage of tumor growth.

While therapy-induced autophagy is conventionally conceived to be cytoprotective in nature, previous studies have identified multiple functions of autophagy, including a nonprotective form, as well as the existence of a switch between the different forms of autophagy. The current work provides further evidence of an autophagic switch, in this case in response to the antitumor drug, cisplatin, in non-small cell lung cancer cells that are either wild-type (p53wt) or functionally null in p53 (crp53), the latter generated using CRISPR/Cas9 technology. Pharmacological and genetic inhibition of autophagy identified nonprotective autophagy in p53wt cells and cytoprotective autophagy in crp53 cells. Furthermore, differences in cisplatin sensitivity between the two cell lines proved to be largely a function of the nature of the autophagy. Specifically, autophagy inhibition in the crp53 cells converts the temporal profile for the loss of cell viability in response to cisplatin to essentially parallel that observed in the p53wt cells. This enhanced sensitivity is due to cisplatin-induced apoptosis that occurs without necessitating the restoration of functional p53. In contrast, inhibition of autophagy has no observable impact on the temporal response profile exhibited in response to cisplatin in the p53wt cells, or the extent of cisplatin-induced apoptosis in the p53wt cells, consistent with the functional definition of nonprotective autophagy. Taken together, our current studies provide evidence that nonprotective autophagy in p53wt non-small cell lung cancer cells can be "switched" to protective autophagy in isogenic crp53 cells, and furthermore that inhibition of cytoprotective autophagy is sufficient to restore cisplatin sensitivity in the crp53 cells, largely through the increased promotion of apoptosis, despite the absence of functional p53., 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 © 2020 Elsevier Inc. All rights reserved.)

Traditional 2D monolayer cell culture model may overestimate chemopreventive agent's response due to lacking physiological relevance in three-dimensional microenvironment. This study was aimed to apply a novel 3D h9e peptide hydrogel cell culture system to evaluate the anticancer efficacy of chemopreventive phenolic acid on hepatocarcinoma HepG2 and colon adenocarcinoma SW480 cells. Both cell lines grew better in this 3D system with better cell growth and longer exponential phase than that in 2D model. Chlorogenic acid (CGA), known as a chemopreventive phenolic acid, at 0-40 μM for 72 h inhibited cell growth but not viability in both HepG2 and SW480 cells. The inhibition was much less potent in 3D system with an IC 50 value of 58.0 ± 15.8 or 285.6 ± 75.4 μM when compared with 2D model with IC 50 of 5.3 ± 0.3 or 12.0 ± 2.5 μM for HepG2 or SW480, respectively. Furthermore, the recovery of cells grown in 3D system after post-CGA appeared faster than 2D model. Taken together, an advanced 3D model has been established with favoring cell growth and less susceptible to inhibitory treatments in contrast to 2D model, thus predict closely to in vivo situation and may bridge the gap of in vitro to in vivo for prescreening chemopreventive agents for cancer prevention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of N,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker were designed and synthesized as tubulin inhibitors and evaluated for their antiproliferative activity in three human cancer cell lines. Most of the target compounds displayed moderate antiproliferative activity, and N-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-amine (10s) was determined to be the most potent compound. Tubulin polymerization and immunostaining experiments revealed that 10s potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Moreover, 10s effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentration- and time-dependent manners. The molecular docking results revealed that 10s could bind to the colchicine binding site of tubulin.

2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ) is a novel synthesized combretastatin A-4 (CA-4) analog that can be classified as a microtubule inhibitor. Our previous study demonstrated that SQ induced G2/M phase arrest and promoted apoptosis progression in breast cancer cells. In the present study, we found that SQ dissociated the MDM2-p53 complex and directly induced MDM2 degradation through the ubiquitin-dependent proteasome pathway in MCF-7 and MDA-MB-231 cells. Further, p53 was activated by SQ through regulation of its transcription, translation, and post-translation modification. More specifically, we demonstrated that SQ induced caspase-dependent but p53-independent apoptosis, and this apoptosis is associated with the inhibition of MDM2. We also showed that SQ exhibited superior in vivo efficacy and low toxicity than CA-4. The immunofluorescence histochemistry study indicated that SQ also inhibited MDM2 expression in vivo. In summary, we report for the first time that SQ shows excellent anti-breast cancer activity in vivo and in vitro and induces p53-independent apoptosis, which is associated with MDM2 inhibition. Therefore, the novel compound SQ has potential for therapeutic treatment of both wild-type and mutant p53 breast cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The objective of the work was to evaluate the potential of hyaluronan-based nanoparticles as tumor-targeting nano-systems for CD44-overexpressed cancer therapy., Methods: The synthesized amphiphilic cholesteryl succinoyl hyaluronan (Chol-Suc-HA) conjugates self-assembled into docetaxel(DTX)-loaded nanoparticles in the aqueous environment. The physiochemical properties of Chol-Suc-HA-DTX NPs were characterized. The in vitro cytotoxicity of Chol-Suc-HA-DTX NPs against MCF-7, 4T1, A549 and L929 cells was evaluated using MTT and LDH assays. Moreover, the cellular uptake mechanism was investigated using the CLSM and flow cytometry. The in vivo animal experiments of Chol-Suc-HA-DTX NPs including pharmacokinetic evaluation, bio-distribution observed by EX vivo NIRF imaging and antitumor efficacy were also carried out in SD rats or 4T1 tumor-bearing BALB/c mice., Results: The self-assembled Chol-Suc-HA-DTX NPs with different degree of substitution (DS) of hydrophobic moiety exhibited high drug loading, uniform particle size distribution and excellent in vitro stability. However, the plasma stability of Chol-Suc-HA-DTX NPs was significantly influenced by the DS of hydrophobic moiety. The higher the DS was, the more stable the NPs were. Cellular uptake demonstrated that Chol-Suc-HA-DTX NPs were internalized into cancer cells via CD44 receptor-mediated endocytosis. Compared with Taxotere®, Chol-Suc-HA-DTX NPs displayed remarkably higher cytotoxicity to CD44-positive cancer cells (MCF-7, 4T1, A549 cells). In vivo animal experiments confirmed that Chol-Suc-HA-DTX NPs with relatively high DS values exhibited prolonged circulation time, excellent tumor-targeting properties and efficient antitumor effects with extremely low systemic toxicity. In addition, blank Chol-Suc-HA NPs also slightly suppressed the tumor growth., Conclusions: Chol-Suc-HA NPs with a suitable DS value portend to be promising drug vehicles for systemic targeting of CD44-overexpressed cancers.

Purpose: The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX)., Methods: Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model., Results: The particle size and zeta potential of HA-CHEMS vesicles were 131.4 ± 6.2 nm and -13.3 ± 0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P < 0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery., Conclusions: This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.

Simple Summary: Tyrosine kinase inhibitors (TKIs) have demonstrated effectiveness in a variety of malignancies. As is the case for many different classes of drugs, tyrosine kinase inhibitors induce autophagy in various tumor cell models. Autophagy is a cellular degradative machinery that can be protective or cytotoxic to the cells, and in some cases, autophagy has no detectable influence on cell sensitivity to chemotherapy. This review demonstrates that cytoprotective and cytotoxic autophagy are the main forms induced by TKIs and that targeting or modulating autophagy can potentially enhance the tumor cell response to tyrosine kinase inhibitors. Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs. [ABSTRACT FROM AUTHOR]

Microtubule poisons, as is the case with other antitumor drugs, routinely promote autophagy in tumor cells. However, the nature and function of the autophagy, in terms of whether it is cytoprotective, cytotoxic or nonprotective, cannot be predicted; this likely depends on both the type of drug studied as well as the tumor cell under investigation. In this article, we explore the literature relating to the spectrum of microtubule poisons and the nature of the autophagy induced. We further speculate as to whether autophagy inhibition could be a practical strategy for improving the response to cancer therapy involving these drugs that have microtubule function as a primary target. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. Importantly, BZML was a poor substrate for P-glycoprotein (P-gp) and inhibited P-gp function by decreasing P-gp expression at the protein and mRNA levels. Cell morphology changes and the expression of cycle- or apoptosis-related proteins indicated that BZML mainly drove A549/Taxol cells to die by mitotic catastrophe (MC), a p53-independent apoptotic-like cell death, whereas induced A549 cells to die by apoptosis. Taken together, our data suggest that BZML is a novel colchicine binding site inhibitor and overcomes MDR in A549/Taxol cells by inhibiting P-gp function and inducing MC. Our study also offers a new strategy to solve the problem of apoptosis-resistance. [ABSTRACT FROM AUTHOR]

Wedelia (Sphagneticola trilobata , Syn. Wedelia trilobata), a notoriously invasive agricultural weed, can inhibit the growth and development of crops in the field. Eight new eudesmanolides (1–8), along with twelve known congeners (9 – 20), were isolated and identified from the flowers of Wedelia. Their chemical structures were elucidated through various spectroscopic techniques. The isolates were tested for anti-proliferative activities against HeLa, HepG 2 , and SGC-7901 tumor cell lines. Most eudesmanolides exhibited significant anti-proliferative activities with good selectivity. Meanwhile, the cells morphology and clonogenic survival assays were observed for compounds 1 – 3. Moreover, compound 6 displayed obvious anti-neuroinflammatory effect by inhibition of NO production in LPS-induced microglia BV-2 cells with the IC 50 value of 11.77 ± 0.83 μM. Hence, this study demonstrated that the eudesmanolides from Wedelia possessed significant antitumor and anti-inflammatory activity, which provided some guides for the further development and a new thinking for its control. Unlabelled Image [ABSTRACT FROM AUTHOR]