UNASSIGNED: To investigate the toxicity of combretastatin A4 phosphate (CA4P) hyaluronic acid (HA) gel nanoparticles (HA-CA4P-NPs) in OSCC (oral squamous cell carcinoma).
UNASSIGNED: Toxicity was investigated using fluorescence microscopy, MTT assay, flow cytometry, and OSCC xenograft mouse models.
UNASSIGNED: Compared with CA4P, HA-CA4P-NPs generated nearly 10 times more fluorescence in OSCC cells. Cytotoxicity assays showed that HACA4P-NPs were more toxic to SCC-4 cells but not to HNECs. Remarkable necrosis was induced in SCC-4 cells after exposure to HA-CA4P-NPs, and related proteins were upregulated. Furthermore, HA-CA4P-NPs significantly reduced the tumour size.
UNASSIGNED: HA-CA4P-NPs improved drug release and delivery, and increased cytotoxicity to cancer cells.

Clinical treatment with the antineoplastic drug irinotecan (IRI) is often hindered by side effects that significantly reduce the quality of life of treated patients. Due to the growing public support for products with Δ9-tetrahydrocannabinol (THC), even though relevant scientific literature does not provide clear evidence of their high antitumour potential, some cancer patients take unregistered preparations containing up to 80 % THC. This study was conducted on a syngeneic colorectal cancer mouse model to test the efficiency and safety of concomitant treatment with IRI and THC. Male BALB/c mice subcutaneously injected with CT26 cells were receiving 60 mg/kg of IRI intraperitoneally on day 1 and 5 of treatment and/or 7 mg/kg of THC by gavage a day for 7 days. Treatment responses were evaluated based on changes in body, brain, and liver weight, tumour growth, blood cholinesterase activity, and oxidative stress parameters. Irinotecan\'s systemic toxicity was evidenced by weight loss and high oxidative stress. The important finding of this study is that combining THC with IRI diminishes IRI efficiency in inhibiting tumour growth. However, further studies, focused on more subtle molecular methods in tumour tissue and analytical analysis of IRI and THC distribution in tumour-bearing mice, are needed to prove our observations.
Kliničko liječenje antineoplastičnim lijekom irinotekanom (IRI) često je otežano nuspojavama koje značajno smanjuju kvalitetu života liječenih bolesnika. Zbog sve veće javne potpore proizvodima s Δ9-tetrahidrokanabinolom (THC), iako relevantna znanstvena literatura ne daje jasne dokaze o njihovu visokom antitumorskom potencijalu, oboljeli od raka uzimaju neregistrirane pripravke koji sadržavaju i do 80 % THC-a. Ova studija provedena je na modelu singeničnoga tumora debelog crijeva u miševa kako bi se testirala učinkovitost i sigurnost istodobnog tretmana irinotekanom i THC-om. Mužjaci BALB/c miševa kojima su supkutano injicirane CT26 stanice primili su 60 mg/kg IRI-ja intraperitonealno prvi i peti dan i/ili 7 mg/kg THC-a oralno svaki dan tijekom sedam dana. Učinkovitost tretmana procijenjena je na temelju promjena u težini tijela, mozga i jetre, rasta tumora, aktivnosti kolinesteraza u krvi i parametara oksidacijskoga stresa. Sistemska toksičnost irinotekana potvrđena je smanjenjem težine miševa i povećanjem parametara oksidacijskoga stresa. Značaj je rezultata ove studije u smanjenoj učinkovitosti IRI-ja u inhibiciji rasta tumora tijekom istodobnog uzimanja s THC-om. Međutim, potrebna su daljnja istraživanja usmjerena na suptilnije molekularne metode u tumorskom tkivu i analitička analiza distribucije IRI-ja i THC-a u miševa s tumorom kako bi se dokazala naša opažanja.

Although it is known that the first case of cancer was recorded in ancient Egypt around 1600 BC, it was not until 1917 during the First World War and the development of mustard gas that chemotherapy against cancer became relevant; however, its properties were not recognised until 1946 to later be used in patients. In this sense, the use of metallopharmaceuticals in cancer therapy was extensively explored until the 1960s with the discovery of cisplatin and its anticancer activity. From that date to the present, the search for more effective, more selective metallodrugs with fewer side effects has been an area of continuous exploration. Efforts have led to considering a wide variety of metals from the periodic table, mainly from the d-block, as well as a wide variety of organic ligands, preferably with proven biological activity. In this sense, various research groups have found an ideal binder in Schiff bases, since their raw materials are easily accessible, their synthesis conditions are friendly and their denticity can be manipulated. Therefore, in this review, we have explored the anticancer and antitumor activity reported in the literature for coordination complexes of d-block metals coordinated with tridentate Schiff bases (O N O and O N N) derived from salicylaldehyde. For this work, we have used the main scientific databases CCDC® and SciFinder®.

Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer activity. The main goal of this work was to combine the two referred structures by synthesizing steroidal oximes and evaluating them in several cancer cell lines. Compounds (17E)-5α-androst-3-en-17-one oxime (3,4 - OLOX), (17E)-3α,4α-epoxy-5α-androstan-17-one oxime (3,4 - EPOX), (17E)-androst-4-en-17-one oxime (4,5 - OLOX) and (17E)-4α,5α-epoxyandrostan-17-one oxime (4,5 - EPOX) were synthesized and their cytotoxicity evaluated in four human cancer cell lines, namely colorectal adenocarcinoma (WiDr), non-small cell lung cancer (H1299), prostate cancer (PC3) and hepatocellular carcinoma (HepG2). A human non-tumour cell line, CCD841 CoN (normal colon cell line) was also used. MTT assay, flow cytometry, fluorescence and hemocompatibility techniques were performed to further analyse the cytotoxicity of the compounds. 3,4 - OLOX was the most effective compound in decreasing tumour cell proliferation in all cell lines, especially in WiDr (IC50 = 9.1 μM) and PC3 (IC50 = 13.8 μM). 4,5 - OLOX also showed promising results in the same cell lines (IC50 = 16.1 μM in WiDr and IC50 = 14.5 μM in PC3). Further studies also revealed that 3,4 - OLOX and 4,5 - OLOX induced a decrease in cell viability accompanied by an increase in cell death, mainly by apoptosis/necroptosis for 3,4 - OLOX in both cell lines and for 4,5 - OLOX in WiDr cells, and by necrosis for 4,5 - OLOX in PC3 cells. These compounds might also exert their cytotoxicity by ROS production and are not toxic for non-tumour CCD841 CoN cells. Additionally, both compounds did not induce haemoglobin release, proving to be safe for intravenous administration. 3,4 - OLOX and 4,5 - OLOX might be the starting point for an optimization program towards the discover of new steroidal oximes for anticancer treatment.

Sorafenib is recommended as the primary therapeutic drug for patients with hepatocellular carcinoma. To discover a new compound that avoids low response rates and toxic side effects that occur in sorafenib therapy, we designed and synthesized new hybrid compounds of sorafenib and 2,4,5-trimethylpyridin-3-ols. Compound 6 was selected as the best of 24 hybrids that inhibit each of the four Raf kinases. The anti-proliferative activity of 6 in HepG2, Hep3B, and Huh7 cell lines was slightly lower than that of sorafenib. However, in H6c7 and CCD841 normal epithelial cell lines, the cytotoxicity of 6 was much lower than that of sorafenib. In addition, similar to sorafenib, compound 6 inhibited spheroid forming ability of Hep3B cells in vitro and tumour growth in a xenograft tumour model of the chick chorioallantoic membrane implanted with Huh7 cells. Compound 6 may be a promising candidate targeting hepatocellular carcinoma with low toxic side effects on normal cells.

A series of novel α-l-threose nucleoside phosphonate analogs, 4(R)-methyl-3-O-phosphonomethyl-α-l-threose nucleosides, were synthesized in multistep sequences starting from d-xylose. The synthetic sequence consisted of the following key stages: (i) the multistep synthesis of 1,2-O-isopropylidenyl-4(R)-methyl-3-O-phosphonomethyl-l-threose, (ii) the transformation of 1,2-O-isopropylidenyl sugar into suitable 1,2-di-O-acyl l-threose precursor, and (iii) the construction of target α-l-threose nucleoside phosphonate analogs by Vorbrüggen glycosidation reaction, deprotection of acyl group, and hydrolysis of diethyl group on phosphonate. The target nucleoside phosphonates were evaluated for their antitumour activities in cell culture-based assays. Compound 8g, 2-fluroadenosine phosphonate, showed remarkable activity against human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values of 0.476 and 0.391 μM, corresponding to 41- and 47-fold higher potency than the reference compound 5-FU, respectively. Subsequent investigations found that the compound 8g can inhibit the proliferation of breast cancer cells and cell cloning. The mechanistic studies indicated that compound 8g could cause DNA damage to breast cancer cells through the ATM-Chk1/Chk2-cdc25c pathway, leading to blockage of the G2/M phase cycle of breast cancer cells, which ultimately led to apoptosis. Moreover, 8g could inhibit the PI3K/AKT signaling pathway and induce apoptosis. These results indicate that compound 8g holds promising potential as an antitumour agent.

(1) Background: Cynara cardunculus L. subsp. scolymus (L.) Hegi, popularly known as artichoke, is an herbaceous plant belonging to the Asteraceae family. Artichoke leaf extracts (ALEs) have been widely used in traditional medicine because of their hepatoprotective, cholagogic, hypoglycaemic, hypolipemic and antibacterial properties. ALEs are also recognized for their antioxidative and anti-inflammatory activities. In this study, we evaluated the cytotoxic, genotoxic, and apoptotic activities, as well as effect on cell growth of ALEs on human colon cancer HT-29 and RKO cells. HT-29 and RKO cells exhibit a different p53 status: RKO cells express the wild-type protein, whereas HT-29 cells express a p53-R273H contact mutant. (2) Methods: Four different ALEs were obtained by sequential extraction of dried artichoke leaves; ALEs were characterized for their content in chlorogenic acid, cynaropicrin, and caffeoylquinic acids. HT-29 and RKO cells were used for in vitro testing (i.e., cytotoxicity and genotoxicity assessment, cell cycle analysis, apoptosis induction). (3) Results: Two out of the four tested ALEs showed marked effects on cell vitality toward HT-29 and RKO tumour cells. The effect was accompanied by a genotoxic activity exerted at a non-cytotoxic concentrations, by a significant perturbation of cell cycle (i.e., with increase of cells in the sub-G1 phase), and by the induction of apoptosis. (4) Conclusions: ALEs rich in cynaropicrin, caffeoylquinic acids, and chlorogenic acid showed to be capable of affecting HT-29 and RKO colon cancer cells by inducing favourable biological effects: cell cycle perturbation, activation of mitochondrial dependent pathway of apoptosis, and the induction of genotoxic effects probably mediated by the induction of apoptosis. Taken together, these results weigh in favour of a potential cancer chemotherapeutic activity of ALEs.

To explore novel antitumor agents with high efficiency and low toxicity, riluzole alkyl derivatives (4a-4i) were synthesized. Their anti-proliferative activities against HeLa, HepG2, SP2/0, and MCF-7 cancer cell lines were assessed by the CCK-8 assay and compared with human normal liver (LO2) cells. Most of them showed potent cytotoxic effects against four human tumor cell lines and low toxic to LO2 cells. In particular, 2-(N-ethylamine)-6-trifluoromethoxy- benzothiazole (4a) showed a IC50 value of 7.76 μmol/L in HeLa cells and was found to be nontoxic to LO2 cells up to 65 μmol/L. Furthermore, flow cytometry indicated that 4a could induce remarkable early apoptosis and G2/M cell cycle arrest in HeLa cells. It also impaired the migration ability of HeLa cells in wound healing assays. Western blot results demonstrated that 4a suppressed Bcl-2 protein expression but increased the level of Bax in HeLa cells, and elevated the Bax/Bcl-2 expression ratio. These new findings suggest that 4a exhibited beneficially anti-cervical cancer effect on HeLa cells by inducing HeLa cell apoptosis.

Human purine nucleoside phosphorylase (HsPNP) belongs to the purine salvage pathway of nucleic acids. Genetic deficiency of this enzyme triggers apoptosis of activated T-cells due to the accumulation of deoxyguanosine triphosphate (dGTP). Therefore, potential chemotherapeutic applications of human PNP inhibitors include the treatment of T-cell leukemia, autoimmune diseases and transplant tissue rejection. In this report, we present the discovery of novel HsPNP inhibitors by coupling experimental and computational tools. A simple, inexpensive, direct and non-radioactive enzymatic assay coupled to hydrophilic interaction liquid chromatography and UV detection (LC-UV using HILIC as elution mode) was developed for screening HsPNP inhibitors. Enzymatic activity was assessed by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx) by LC-UV. A small library of 6- and 8-substituted nucleosides was synthesized and screened. The inhibition potency of the most promising compound, 8-aminoinosine (4), was quantified through Ki and IC50 determinations. The effect of HsPNP inhibition was also evaluated in vitro through the study of cytotoxicity on human T-cell leukemia cells (CCRF-CEM). Docking studies were also carried out for the most potent compound, allowing further insights into the inhibitor interaction at the HsPNP active site. This study provides both new tools and a new lead for developing novel HsPNP inhibitors.

BACKGROUND: The past few years have witnessed an increasing interest in essential oils (EOs) as potential therapeutic agents against a wide variety of pathologies, including cancer. EOs extracted from Ridolfia segetum (L.) Moris (R. segetum) are a clear example of a phytoproduct with therapeutic applications, as it is widely used in traditional medicine due to its antioxidant and anti-inflammatory properties, and these properties were already validated by previous studies. Although, it is well established that inflammation is a key hallmark of cancer, with a key role promoting tumorigenesis, and being chronic inflammation often associated with tumorigenic processes, there are no previous studies regarding the assessment of the antitumoural potential of R. segetum EOs.
OBJECTIVE: The present study intends to be the first to evaluate the antitumoural proprieties of R. segetum EO phytoproducts in cancer cell models.
METHODS: For this, R. segetum EOs were extracted from plants collected at either flowering (RS_Fl) or fruiting (RS_Fr) stage. The impact on proliferation and viability of treatment with R. segetum EO extracts was assessed using in vitro 2D and 3D models.
RESULTS: Both R. segetum EOs presented effective antiproliferative/viability effects, evidence noted by low IC50 values in 2D models, and significant reduction of spheroid size in 3D in vitro models. Mechanistically, treatment with R. segetum EOs was associated with an altered G1 (associated with p21 stabilisation), and subsequent induction of apoptosis.
CONCLUSIONS: Overall, these results indicate that R. segetum EOs have potential as suitable antitumoural therapeutic agents.