L1210 Leukemia Research Articles

Synthesis, QTAIM, anticancer activity analysis of pyrrole-imidazole/benzimidazole derivatives and investigation of their reactivity properties using DFT calculations and molecular docking

As part of our ongoing investigation into pyrrole derivatives, we here present the synthesis, spectroscopic characterization, QTAIM, reactivity, anticancer activity, and comparative experimental and computational analysis of pyrrole-imidazole ((3l), (3p)) and benzimidazole derivatives ((3h), (3i), (3j), (3k), (3m), (3n), (3o)). All synthesized compounds (3h-3p) have been well characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, Mass spectrometry). The experimental 1H and 13C NMR chemical shift values of synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives have been well corroborated with computed chemical shifts. The vibrational analysis for four derivatives of pyrrole-benzimidazole (3m), (3n), (3o), and pyrrole-imidazole (3p) has the suitability for dimer formation in solid state by intermolecular heteronuclear hydrogen bonding (N–H···O) and the interaction energy of dimers are calculated to be 10.88, 11.70, 9.89 and 10.72 kcal/mol, using DFT. After basis-set superposition error (BSSE) correction, the interaction energies of dimers were found to be 11.12, 12.11, 10.13, and 11.52 kcal/mol. Estimated intermolecular H-bond in (3m-3n) compounds were found to be -13.38, -12.86, -11.02, and -11.28 kJ/mol using QTAIM. All the synthetic pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives exhibit strong antileukemia activity in vitro against the proliferative cell line L1210 leukemia cells. A dataset of investigated compounds was subjected for molecular modelling simulation against three distinct proteins (SYK, PI3K, and BTK), which was found to be highly implicated in the favourable interaction between the compounds and their target proteins in every instance. The synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives shown favourable interactions with their target proteins, with high activity and binding free energy values falling between 15.22 and 13.43 and -7.4 and -9.8 kcal/mol, respectively. The structure of pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives is thoroughly examined, and several parameters are proposed here to improve their anticancer activity.

A macromolecular Gleditsia Saponin induces apoptosis of leukemia cells through Fas-mediated death receptor pathway and mitochondrial pathway

Gleditsia sinensis Lam., a natural product derived from medicine and food, exhibits outstanding biological activity, with its primary active component being triterpenoid saponin. In this study, a new macromolecular Gleditsia Saponin (GS) with a molecular weight of 27.562 kDa was extracted from Gleditsia sinensis Lam.. The study focused on examining the impact of GS on the suppression of cell growth and the initiation of apoptosis in leukemia K562 and L1210 cells. The results showed that GS notably suppressed the growth of leukemia cells in a manner reliant on concentration. Morphological and Annexin V-FITC/PI staining analyses revealed characteristic features of apoptosis in leukemia cells treated with GS. Moreover, cell cycle analysis indicated that GS effectively arrested leukemia cell progression at the G0/G1 phase. Mitochondrial membrane potential (ΔΨm) was disrupted, and abnormal accumulation of reactive oxygen species was also detected. In addition, GS could induce cell apoptosis through the Fas-mediated death receptor pathway and mitochondrial pathway, leading to the blocking of leukemia cells in the G1 phase. In summary, these results provide theoretical backing and fresh perspectives for the development and utilization of GS as a functional health food.

Ultraviolet Light-Emitting Diode Radiation Kills Leukemia Cells Without Affecting Hematopoiesis of Hematopoietic Stem Cells in Mice.

The eradication of leukemia cells while sparing hematopoietic stem cells in the graft before autologous hematopoietic stem cell transplant is critical to prevention of leukemia relapse. Proliferating cells have been shown to be more prone to apoptosis than differentiated cells in response to ultraviolet radiation; however, whether leukemia cells are more sensitive to ultraviolet LED radiation than hematopoietic stem cells remains unclear. We compared the in vitro responses between murine leukemia L1210 cells and murine hematopoietic stem cells to 280-nm ultraviolet LED radiation. We also investigated the effects of ultraviolet LED radiation on the tumorigenic and metastatic capacity of L1210 cells and hematopoietic stem cell hematopoiesis in a mouse model of hematopoietic stem cell transplant. L1210 cells were more sensitive to ultraviolet LED radiation than hematopoietic stem cells in vitro, as evidenced by significantly reduced colony formation rates and cell proliferation rates, along with remarkably increased apoptosis rates in L1210 cells. Compared with corresponding unirradiated cells, ultraviolet LED-irradiated L1210 cells failed to generate palpable tumors in mice, whereas ultraviolet LED-irradiated bone marrow cells restored hematopoiesis in vivo. Furthermore, transplant with an irradiated mixture of L1210 cells and bone marrow cells showed later onset of leukemia, milder leukemic infiltration, and prolonged survival in mice, compared with unirradiated cell transplant. Our results suggest that ultraviolet LED radiation can suppress the proliferative and tumorigenic abilities of leukemia cells without reducing the hematopoietic reconstitution capacity of hematopoietic stem cells, serving as a promising approach to kill leukemia cells in autograft before autologous hematopoietic stem cell transplant.

Anti-Cancer Effects of CDK4/6 Inhibitor LEE011 and Chemotherapy Drugs on Lymphocytic Leukemia L1210 Cells.

Chronic lymphocytic leukemia is a slowly-progressing disease in which symptoms often do not manifest until years after disease onset. In advanced stages, infection and bleeding are common. Past studies have shown that the interaction between CDK4/6 inhibitors and chemotherapy drugs can enhance the anti-tumor efficacy of drugs and limit toxicity. Therefore, in this study, the treatment effects of combining the CDK4/6 inhibitor LEE011 with chemotherapy drugs bendamustine or hydroxyurea were investigated in vitro. The mouse lymphocytic leukemia cell line L1210 was treated with LEE011 combined with hydroxyurea or bendamustine. Western blot and flow cytometry were performed to elucidate the mechanisms behind tumor suppression. LEE011 combined with hydroxyurea or bendamustine significantly inhibited proliferation of L1210 cell lines in a concentration- and time-dependent manner as well as increased the arrest of cells in G1 and S phases. The combination of LEE011 with hydroxyurea also reduced the phosphorylation of Rb while increased the expression of total Rb protein. Furthermore, reduced expression of GPX4, which is a key protein in ferroptosis, indicates that the tumor suppression effects of this drug combination could involve ferroptosis. CDK4/6 inhibitor LEE011 treatment alone may not be a suitable treatment option for lymphocytic leukemia; however, our findings in vitro support the combination of LEE011 with chemotherapy drugs to enhance anti-tumor activity in lymphocytic leukemia.

N-Desmethylmajusculamide B, a lipopeptide isolated from the Okinawan cyanobacterium Okeania hirsuta.

A new lipopeptide, N-desmethylmajusculamide B (1), was isolated from the Okinawan cyanobacterium Okeania hirsuta along with 2 known compounds majusculamide A (2) and majusculamide B (3). The planar structure of (1) was elucidated by a detailed analysis of mass spectrometry and nuclear magnetic resonance spectra. The absolute configurations of the amino acid residues were determined using Marfey's analysis. The configuration of C-16 in the α-methyl-β-keto-decanoyl moiety was determined unambiguously to be S by conducting a semisynthesis of N-desmethylmajusculamide B from 3. The cytotoxicity against mouse L1210 leukemia cells was evaluated for majusculamides (1-3).

Cytotoxicity and antitumor activity of sesquiterpene lactones. Structure, activity

The article discusses the results of 19 samples screening of sesquiterpene γ-lactones argolide, grosheimin, estafiatin, and their derivatives for cytotoxicity and antitumor activity. The research results indicate significant cytotoxicity and selectivity of the action of sesquiterpene γ-lactones and their derivatives against most tumor cell lines. Aim. The purpose of this study is to study the cytotoxicity and antitumor activity of the sesquiterpene γ-lactones argolide, grosheimin, estafiatin and their chemically modified derivatives, as practically renewable materials. Methods. The cytotoxicity of the compounds was determined using vero cells, THP-1, Pliss lymphosarcoma cell lines, Walker carcinosarcoma, sarcoma 45, sarcoma-180, alveolar liver cancer PC-1, P-388 leukemia, L-1210 leukemia, and resistant to 5-fluorouracil sarcoma 45. The antitumor activity of the samples was studied in in vivo experiments on white outbred rats with transplanted tumor strains and was assessed by inhibition of tumor growth and the magnitude of the increase in average life expectancy. Statistical processing of the results was carried out using the program “GraphPad Prism v. 6.0" (GraphPad Software Inc., USA). Conclusion. When determining cytotoxicity in in vitro samples of the sesquiterpene γ-lactones argolide, grosheimin, and estafiatin showed selectivity of their action on cells of 8 tumor lines, on cells of human acute monocytic leukemia THP-1 and in relation to the larvae of sea crustaceans Artemia salina (Leach). Samples of argolide, 8-acetylgrosheimin, 13-morpholinogrosheimin, 3-keto-4-methylene-cis-guaianolide, 3α-acetoxyisozaluzanin C, and 10α(14)-epoxy-1,5,7α,4,6β(H)-guai-11(13)-en-4(3),6(12)-diolide in experiments in vivo possessed high antitumor activity against transplantable tumor strains of Pliss lymphosarcoma, Walker carcinosarcoma, sarcoma 45, sarcoma 37, sarcoma 180, alveolar liver cancer PC-1, leukemia P-388 and L-1210, resistant to 5-fluorouracil sarcoma 45

Cannabimimetic N-Stearoylethanolamine as "Double-Edged Sword" in Anticancer Chemotherapy: Proapoptotic Effect on Tumor Cells and Suppression of Tumor Growth versus Its Bio-Protective Actions in Complex with Polymeric Carrier on General Toxicity of Doxorubicin In Vivo.

This study reports a dose-dependent pro-apoptotic action of synthetic cannabimimetic N-stearoylethanolamine (NSE) on diverse cancer cell lines, including multidrug-resistant models. No antioxidant or cytoprotective effects of NSE were found when it was applied together with doxorubicin. A complex of NSE with the polymeric carrier poly(5-(tert-butylperoxy)-5-methyl-1-hexen-3-yn-co-glycidyl methacrylate)-graft-PEG was synthesized. Co-immobilization of NSE and doxorubicin on this carrier led to a 2-10-fold enhancement of the anticancer activity, particularly, against drug-resistant cells overexpressing ABCC1 and ABCB1. This effect might be caused by accelerated nuclear accumulation of doxorubicin in cancer cells, which led to the activation of the caspase cascade, revealed by Western blot analysis. The NSE-containing polymeric carrier was also able to significantly enhance the therapeutic activity of doxorubicin in mice with implanted NK/Ly lymphoma or L1210 leukemia, leading to the complete eradication of these malignancies. Simultaneously, loading to the carrier prevented doxorubicin-induced elevation of AST and ALT as well as leukopenia in healthy Balb/c mice. Thus, a unique bi-functionality of the novel pharmaceutical formulation of NSE was revealed. It enhanced doxorubicin-induced apoptosis in cancer cells in vitro and promoted its anticancer activity against lymphoma and leukemia models in vivo. Simultaneously, it was very well tolerated preventing frequently observed doxorubicin-associated adverse effects.

A Novel Form of Arginine-Chitosan as Nanoparticles Efficient for siRNA Delivery into Mouse Leukemia Cells.

The modification of chitosan (CS) has greatly expanded its application in the field of medicine. In this study, low-molecular-weight chitosan was modified with arginine (Arg) by a simple method. The identification by the Fourier transform infrared spectra (FTIR) showed that Arg was successfully covalently attached to the CS. Interestingly, Arg-CS was identified as nanoparticles by atomic force microscopy (AFM) and transmission electron microscopy (TEM), whose particle size was 75.76 ± 12.07 nm based on Dynamic Light Scattering (DLS) characterization. Then, whether the prepared Arg-CS nanoparticles could encapsulate and deliver siRNA safely was investigated. Arg-CS was found to be able to encapsulate siRNAs in vitro via electrostatic interaction with siRNA; the Arg-CS/siRNA complex was safe for L1210 leukemia cells. Therefore, modification of chitosan by Arg produces novel nanoparticles to deliver siRNA into leukemia cells. This is the first time to identify Arg-CS as nanoparticles and explore their ability to deliver Rhoa siRNA into T-cell acute lymphoblastic leukemia (T-ALL) cells to advance therapies targeting Rhoa in the future.

A novel costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4+ T cell vaccine efficiently enhances anti-leukemia immunity.

Previous studies demonstrated that CD4+ T cells can uptake tumor antigen-pulsed dendritic cell-derived exosomes (DEXO), which harbor tumor antigen peptide/pMHC I complex and costimulatory molecules and show potent effects on inducing antitumor immunity. However, in preliminary study, CD4+ T cells targeted by leukemia cell-derived exosomes (LEXs) did not show the expected effects in inducing effective anti-leukemia immunity, indicating that LEX is poorly immunogenetic largely due to an inadequate costimulatory capacity. Therefore, LEX-based anti-leukemia vaccines need to be optimized. In this study, we constructed a novel LEX-based vaccine by combining CD4+ T cells with costimulatory molecules gene-modified LEXs, which harbor upregulated CD80 and CD86, and the anti-leukemia immunity of CD80 and CD86 gene-modified LEX-targeted CD4+ T cells was investigated. We used lentiviral vectors encoding CD80 and CD86 to successfully transduced the L1210 leukemia cells, and the expression of CD80 and CD86 was remarkably upregulated in leukemia cells. The LEXs highly expressing CD80 and CD86 were obtained from the supernatants of gene-transduced leukemia cells. Our data have shown that LEX-CD8086 could promote CD4+ T cell proliferation and Th1 cytokine secretion more efficiently than control LEXs. Moreover, CD4+ TLEX-CD8086 expressed the acquired exosomal costimulatory molecules. With acquired costimulatory molecules, CD4+ TLEX-CD8086 can act as APCs and are capable of directly stimulating the leukemia cell antigen-specific CD8+ CTL response. This response was higher in potency compared to that noted by the other formulations. Furthermore, the animal study revealed that the CD4+ TLEX-CD8086 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice than other formulations did in both protective and therapeutic models. In conclusion, this study revealed that CD4+ TLEX-CD8086 could effectively induce more potential anti-leukemia immunity than LEX-CD8086 alone, suggesting that the utilization of a costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4+ T cell vaccine may have promising potential for leukemia immunotherapy.

Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles

Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice.
 Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an in­travenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%).
 Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 sub­stance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C<42%).
 Conclusion: The presented results suggest possible effectiveness of LCS-1208 in treatment of colon malignant tumors of humans.

Application of Multivariate Adaptive Regression Splines (MARSplines) for Predicting Antitumor Activity of Anthrapyrazole Derivatives.

An approach using multivariate adaptive regression splines (MARSplines) was applied for quantitative structure–activity relationship studies of the antitumor activity of anthrapyrazoles. At the first stage, the structures of anthrapyrazole derivatives were subjected to geometrical optimization by the AM1 method using the Polak–Ribiere algorithm. In the next step, a data set of 73 compounds was coded over 2500 calculated molecular descriptors. It was shown that fourteen independent variables appearing in the statistically significant MARS model (i.e., descriptors belonging to 3D-MoRSE, 2D autocorrelations, GETAWAY, burden eigenvalues and RDF descriptors), significantly affect the antitumor activity of anthrapyrazole compounds. The study confirmed the benefit of using a modern machine learning algorithm, since the high predictive power of the obtained model had proven to be useful for the prediction of antitumor activity against murine leukemia L1210. It could certainly be considered as a tool for predicting activity against other cancer cell lines.

Cytotoxic activity of Cantigi leaf extract (Vaccinium varingiaefolium Blume Miq.) on HeLa cervical cancer cells and A549 lung cancer cells

Background: Cervical and lung cancer cases in 2018-2020 have increased worldwide and in Indonesia. Cancer treatment often involves multidisciplinary approaches and is uncomfortable. Therefore, alternative medicine from natural ingredients is needed. Previous studies showed that the Cantigi leaf ethyl acetate extract has cytotoxic activity categorised as very strong on L1210 leukaemia cells (IC50 of 8.29 ppm) and strong on MCF-7 cells (IC50 of 75.23 ppm) and T47D cells (IC50 of 88.89 ppm), but no reports exist on HeLa and A549 cells. Objective: To determine the cytotoxic activity of the ethyl acetate extract of Cantigi leaf on HeLa cells and A549 cells. Methods: Powdered dry young Cantigi leaves were macerated with hexane, then ethyl acetate. After vacuum evaporation, the dry extract was characterised and tested for its cytotoxic activity on HeLa cells and A549 cells using the MTT method. Results: The ethyl acetate extract colour was dark green with a distinctive Cantigi odour; it had a water content of 4.3% and an acidic pH of 2.87. It showed functional groups of O-H, C-H (aliphatic), C-H (hydrocarbon), C=N, C=O, and C=C. Finally, the IC50 of the ethyl acetate extract on A549 cells was 74.74±5.29 ppm, while on the HeLa cells, it was 79.69±2.54 ppm. Conclusion: The ethyl acetate extract of Cantigi leaves showed potent in vitro cytotoxic activity on HeLa cervical cancer cells and A549 lung cancer cells.

Isolation and Structure Elucidation of New Cytotoxic Macrolides Halosmysins B and C from the Fungus Halosphaeriaceae sp. Associated with a Marine Alga.

Two new cytotoxic metabolites, halosmysins B and C, have been isolated from the fungus Halosphaeriaceae sp. OUPS-135D-4 separated from the marine alga Sargassum thunbergii. These chemical structures have been elucidated by 1D and 2D NMR, and HRFABMS spectral analyses. The new compounds had the same 14-membered macrodiolide skeleton as halosmysin A, which was isolated from this fungal strain previously. As the unique structural feature, a diketopiperazine derivative and a sugar are conjugated to the 14-membered ring of halosmysins B and C, respectively. The absolute stereostructures of them were elucidated by the chemical derivatization such as a hydrolysis, the comparison with the known compounds (6R,11R,12R,14R)-colletodiol and halosmysin A, and a HPLC analysis of sugar. In addition, their cytotoxicities were assessed using murine P388 leukemia, human HL-60 leukemia, and murine L1210 leukemia cell lines. Halosmysin B was shown to be potent against all of them, with IC50 values ranging from 8.2 ± 1.8 to 20.5 ± 3.6 μM, though these values were slightly higher than those of halosmysin A.

In Vitro Cytotoxic Activity Test of Tampa Badak (Voacanga foetida (Blume) Leaves on L1210 Leukemia

The Voacanga foetida (Blume) Rolfe leaves have cytotoxic activity based on our previous research, namely the Brine Shrimps Lethality Test on ethanol extract. This study tested the anticancer activity of the extract and leaf fraction of Voacanga foetida in vitro on L1210 leukemia cells using the direct cell count method and doxorubicin positive control. The results showed that the methanol extract, butanol, ethyl acetate, and hexane fractions, as well as isolated compounds Tb1, Tb2, and Tb3 leaves from Voacanga foetida , had IC 50 values of 4.4; 9; 8.4; 16.8; 0.9; 1.8; and 1.1 ppm, compared with doxorubicin with an IC 50 value of 0.2 ppm. Based on the IC 50 value, it showed that the extract, fraction and isolated compounds of Voacanga foetida had a strong cytotoxic effect, as evidenced by the IC 50 value < 30 ppm for each test concentration.

The Effect of Novel Phosphodiesterase 4 Inhibitor ZL-n-91 to the Proliferation of Leukemia Cells

To investigate the inhibitory effects of novel phosphodiesterase 4 inhibitor ZL-n-91 to the proliferation of leukemia cells L1210 and K562. CCK-8 method was used to detect the effect of ZL-n-91 to the proliferation of L1210 and K562 cells, and the proliferation rate, IC50 were calculated. The effects of ZL-n-91 to the cycle of L1210 and K562 cells was detected by PE single staining, and the effects of ZL-n-91 to the apoptosis of L1210 and K562 cells was detected by PE/7AA-D double staining. Western blot was used to detect the effect of ZL-n-91 to the expression levels of apoptosis related proteins. Subcutaneous tumor transplantation model of acute lymphoblastic leukemia L1210 was established in the nude mice, and the inhibitory effect of oral administration of ZL-n-91 to the xenograft was observed. ZL-n-91 showed a significant inhibitory effect to the proliferation of leukemia cells L1210 and K562 in a dose-dependent manner (P<0.001). After treated by ZL-n-91, the leukemia cells L1210 and K562 in the S-phase in cell cycle decreased significantly compared with those in control group (P<0.01). The apoptosis of leukemia cells L1210 and K562 could be induced by ZL-n-91 (P<0.001), and the expression level of apoptosis related protein BAX significantly increased. In the animal experiment, the result showed that ZL-n-91 could significantly inhibit the growth of subcutaneously transplantation tumor (P<0.05). The novel phosphodiesterase 4 inhibitor ZL-n-91 can effectively inhibit the proliferation of leukemia cells L1210 and K562, which has the potential of anti-leukemia drug development.

A rohitukine derivative IIIM-290 induces p53 dependent mitochondrial apoptosis in acute lymphoblastic leukemia cells.

Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo. We found that IIIM-290 induced apoptosis through upregulation of different apoptotic proteins like PUMA, BAX, cytochrome c, cleaved (active) caspase-3, and cleaved PARP in MOLT-4 cells. Moreover, IIIM-290 abated mitochondrial membrane potential, elevated calcium levels, reactive oxygen species, and arrested growth of MOLT-4 cells in the synthesis (S) phase of the cell cycle. Interestingly, the elevation in proapoptotic markers was p53 dependent-the silencing of p53 abrogated apoptosis (programmed cell death) triggered by IIIM-290 in MOLT-4 cells. Furthermore, IIIM-290 significantly enhanced the survival of animals with P388 and L1210 leukemia. Thus, our results put IIIM-290 as a potential candidate for the anticancer lead.

Marine Antitumor Peptide Dolastatin 10: Biological Activity, Structural Modification and Synthetic Chemistry.

Dolastatin 10 (Dol-10), a leading marine pentapeptide isolated from the Indian Ocean mollusk Dolabella auricularia, contains three unique amino acid residues. Dol-10 can effectively induce apoptosis of lung cancer cells and other tumor cells at nanomolar concentration, and it has been developed into commercial drugs for treating some specific lymphomas, so it has received wide attention in recent years. In vitro experiments showed that Dol-10 and its derivatives were highly lethal to common tumor cells, such as L1210 leukemia cells (IC50 = 0.03 nM), small cell lung cancer NCI-H69 cells (IC50 = 0.059 nM), and human prostate cancer DU-145 cells (IC50 = 0.5 nM), etc. With the rise of antibody-drug conjugates (ADCs), milestone progress was made in clinical research based on Dol-10. A variety of ADCs constructed by combining MMAE or MMAF (Dol-10 derivatives) with a specific antibody not only ensured the antitumor activity of the drugs themself but also improved their tumor targeting and reduced the systemic toxicity. They are currently undergoing clinical trials or have been approved for marketing, such as Adcetris®, which had been approved for the treatment of anaplastic large T-cell systemic malignant lymphoma and Hodgkin lymphoma. Dol-10, as one of the most medically valuable natural compounds discovered up to now, has brought unprecedented hope for tumor treatment. It is particularly noteworthy that, by modifying the chemical structure of Dol-10 and combining with the application of ADCs technology, Dol-10 as a new drug candidate still has great potential for development. In this review, the biological activity and chemical work of Dol-10 in the advance of antitumor drugs in the last 35 years will be summarized, which will provide the support for pharmaceutical researchers interested in leading exploration of antitumor marine peptides.

Оценка противоопухолевой активности ряда производных 4-аминопиперидина, низкомолекулярных ингибиторов Hsp70, на перевиваемых опухолях мышей

Low molecular weight compounds targeting chaperone proteins Hsp90 and Hsp70 have opened up a new avenue in the therapy of neoplasms. In 2020, we tested 3 Hsp70 inhibitors from the class of 4-aminopiperidine derivatives for their antitumor activity on in vivo models. The list of the tested compounds included N-(2-chlorobenzyl)-N-ethyl-1-(2-(methylthio)pyrimidin-4-yl)piperidin-4-amine (compound 1), 4-((methyl(1-(2-(methylthio)pyrimidin-4-yl) piperidin-4-yl)amino)methyl) benzonitrile (compound 2) and N-(2,6- dichlorobenzyl)-1-(1-(2-(ethylthio)pyrimidin-4-yl)piperidin-4-yl)-N-methylmethaneamine (compound 3). The aim of this study was to compare the efficacy of 4-aminopiperidine derivatives in vivo using the models of transplantable murine L1210 lymphocytic leukemia and B16 melanoma. Compounds 2 and 3 used in combination with cyclophosphamide exhibited high cytotoxic activity (р = 0.05) against L1210 leukemia (an 80-82% increase in survival time) and B16 melanoma (98-99.7% tumor growth delay). For L1210 lymphocytic leukemia, compounds 2 and 3 used in combination with cyclophosphamide fell into the low (+) therapeutic potential category. For B16 melanoma, compounds 1, 2 and 3 used in combination with cyclophosphamide fell into either low (+) or moderate (++) therapeutic potential categories. On the whole, the tested doses of the compounds used in combination with cyclophosphamide hold promise for the therapy of L1210 leukemia and B16 melanoma in mouse models. Our findings confirm the potential of low molecular weight Hsp70 inhibitors for combination chemotherapy against cancer.

Synthesis, molecular docking, and preliminary cytotoxicity study of some novel 2-(naphthalen-1-yl)-methylimidazo[2,1-b][1,3,4]thiadiazoles

A series of 2-(naphthalen-1-yl)-methyl-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives was prepared and studied for cytotoxicity against murine leukemia L1210, human cervix carcinoma HeLa, and human T-lymphocyte CEM cell lines. The preliminary study showed that compounds 5g, 6g, 7a-c, 7e, and 8e were more potent among the tested compounds. The pharmacokinetic properties of all compounds were then investigated with FAF-Drugs, a tool for prediction of ADME and toxicity. Finally, in order to support in vitro studies, molecular docking studies were performed by using AutoDock Vina with a Lamarckian genetic algorithm to determine whether or not the synthesized compounds could be used as inhibitors for the protein structure 1m17 (EGFR). The docking scores of many compounds were found to be higher than [6,7-bis(2-methoxy-ethoxy)quinazoline-4-yl]-(3-ethynyl phenyl)amine, an inhibitor of the 1m17 EGFR receptor. Among the selected compounds 7b, 7c, 7e, 7f, 7g, and 8g showed better stability in the molecular dynamics simulation study.

The effect of lipid derivative of anti-tumor drug sarcolysin embedded in phospholipid nanoparticles in the experiments in vivo

To improve the therapeutic properties of the antitumor agent Sarcolysin, we have previously developed and characterized a dosage form representing its ester conjugate with decanol embedded in ultra-small phospholipid nanoparticles less than 30 nm in size ("Sarcolysin-NP"). The effect of the resulting composition was investigated in vivo in comparison with the free substance of sarcolysin. The composition intravenous administration to mice showed an improvement in the pharmacokinetic parameters of sarcolysin associated with its initial higher (by 22%) level in the blood and prolonged circulation, which was also observed in mice with P388 tumor. In mice with three types of tumors - lymphocytic leukemia P388, lymphocytic leukemia L1210, and adenocarcinoma of the mammary gland Ca755 - administration of two doses of sarcolysin over a period of 7 days showed its predominant antitumor effect. The maximum tumor growth inhibition was noted for lymphocytic leukemia L1210 and adenocarcinoma of the mouse mammary gland Ca755 (at a dose of Sarcolysin-NP - 8,4 mg/kg), which was higher in comparison with free substance by more than 24% and 17%, respectively. Differences in the life span of the treated animals were revealed significantly at a dose of 10 mg/kg and amounted to 25% and 17,4% for lymphocytic leukemia P388 and L1210, respectively, and 11% for adenocarcinoma Ca755. In an experiment on rats, acute toxicity of Sarcolysin-NP administered intravenously showed that an average LD50 value 2-3 times exceeded a similar parameter for commercial preparations of free sarcolysin (Melphalan and Alkeran), which indicates its lower toxicity.