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The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo. Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools ; The research leading to these results has received funding from the following FEDER cofunded-grants. From CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01, AGL2014-58210-R, and Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD. From the European Union's Seventh Framework Programme managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement 312184 PHARMASEA. M.R.S. is an I2C predoctoral fellow. From CAPES Foundation, Brazil (scholarship process: BEX 10184-13-9) ; SI

AbstractUterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control (p < 0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC (p < 0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.

Shu-De Feng,1,* Ziming Mao,2,* Chunying Liu,2,* Yu-Song Nie,1 Bin Sun,2 Minggao Guo,3 Changqing Su2 1Department of General Surgery, Jiangsu Armed Police General Hospital, Yangzhou, Jiangsu, China; 2Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai, China; 3Department of General Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China *These authors contributed equally to this work Background: Pancreatic adenocarcinoma (PAC) is one of the most fatal cancers due to its high degree of malignancy, increasing incidence, high mortality, and unsatisfactory treatment efficacy. Evidence has suggested that numerous microRNAs (miRNAs), including miR-126 and miR-34a, have potent tumor-suppressing effects on PAC, implicating a possible application of miRNA in tumor therapy. However, the therapeutic effect of a single miRNA on pancreatic cancer is limited.Methods: We simultaneously delivered miR-126 and miR-34a into PAC cells by a carcinoem­bryonic antigen promoter-driven oncolytic adenovirus (AdCEAp-miR126/34a), and examined the antitumor efficacy of the therapeutic system in in vitro and in vivo experiments.Results: In vitro cytological experiments found that the expression levels of miR-126 and miR-34a were specifically increased in the AdCEAp-miR126/34a-infected PAC cells, and the antitumor efficacy was enhanced in aspects of cancer cell viability, migration, invasion, and apoptosis, by synergistically combining the antitumor effects of overexpressed miR-126 and miR-34a and the oncolytic effect of viral replication specifically in PAC cells. The expression levels of miR-126 target genes (vascular endothelial growth factor-A and SOX2) and miR-34a target genes (cyclin D1, E2F1, and Bcl-2) were markedly decreased in the PAC cells after being infected with AdCEAp-miR126/34a. Notable suppression of the therapeutic system on tumor growth was also proven in established PAC xenograft tumor models in nude mice, which demonstrated that the combination of miR-126 and miR-34a exerts more effective antitumor outcomes than a single miRNA.Conclusion: The therapeutic system co-expressing miR-126 and miR-34a mediated by oncolytic adenovirus is a promising system for PAC target therapy. Keywords: pancreatic cancer, miR-126, miR-34a, oncolytic adenovirus, target therapy

Xiao Lu,1,* Dong Zhou,1,* Bing Hou,1 Quan-Xing Liu,1 Qian Chen,2 Xu-Feng Deng,1,3 Zu-Bin Yu,1 Ji-Gang Dai,1 Hong Zheng1 1Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China; 2Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China; 3Department of Cardiothoracic Surgery, First People's Hospital of Zunyi, Guizhou, People's Republic of China *These authors contributed equally to this work Background: Chemotherapy is still the primary adjuvant strategy of cancer therapy; however, the emergence of multi-drug resistance has been a cause for concern. Autophagy has been demonstrated to have a protective role against chemotherapeutic drugs in cancer cells, and autophagy inhibition is generally considered to be a promising therapeutic strategy. However, the paucity of effective and specific autophagy inhibitors limits its application. Purpose: The objective of this study was to explore the effect of DCA, small molecular antitumor agent, on the autophagy regulation and chemosensitization in NSCLC cells. Methods: We investigated the autophagy regulation of dichloroacetate (DCA) by laser confocal microscopy and western blotting in A549 and H1975 cell lines. The MTT assay and flow cytometry was performed for explore the chemosensitization effectiveness of DCA. The results were verified with subcutaneous tumor model in nude mice and the immunohistochemistry was applied for assessing the level of cell apoptosis and autophagy in vivo post treatment. Results: We found that DCA, which exhibited antitumor properties in various carcinoma models, induced apoptosis of non-small cell lung cancer cells (NSCLC) by inhibiting cancer cell autophagy. Furthermore, Perifosine, an AKT inhibitor, can greatly weaken the capacity of inducing apoptosis by DCA. The results indicate that the AKT-mTOR pathway, a main negative regulator of autophagy, is involved in the DCA-induced inhibition of autophagy. Then, we detected the effectiveness of autophagy inhibition by DCA. When used in co-treatment with the chemotherapeutic drug paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited proliferation in A549 and H1975 cells. The results of the xenograft experiment demonstrate that co-treatment of PTX and DCA can significantly decrease cell proliferation in vivo and prolong the survival of mice. Conclusion: Our results suggest that DCA can inhibit cell autophagy induced by chemotherapeutics, providing a new avenue for cancer chemotherapy sensitization. Keywords: DCA, autophagy, multi-drug resistance, non-small-cell lung cancer, paclitaxel, xenograft nude mice, chemosensitization

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment. ; S.R.P.'s laboratory is partially funded by funds from the Spanish National Research and Development Plan, Instituto de Salud Carlos III and FEDER [PI17/02303 to S.R.P]; R.T.R. is supported by a fellowship from the AECC scientific foundation; J.M.B. is supported by Spanish Ministry of Education, Culture and Sport [FPU15/01978]; J.B.'s laboratory is partially funded by FEDER funds, H2020 BRIDGES project and the Spanish Network on Rare Diseases (CIBERER) [FIS PI16/00440]; Faculty of Medicine at the Norwegian University of Science and Technology and the Central Norway Regional Health Authority supports [46056921 to A.S. and H.E.K.]; Svanhild and Arne Must's Fund for Medical Research (to A.S. and H.E.K.); Norwegian Research Council (to T.V.); SIN-TEF SEP project 102020885 (to T.V.); Vinnova (to A.C.K and P.S.); the Torsten and Ragnar Soderberg Foundation (to T.H.) and the Helleday Foundation (to C.B.). Funding for open access charge and project support: European Union's Horizon 2020 research and innovation programunder the Marie Sklodowska-Curie grant agreement [722729 to A.P., B.M.F.H., T.H.]; European Research Council [ERC TAROX-695376 to T.H.]; Swedish Research Council (to T.H. and P.S.); Swedish Cancer Society (to T.H. and P.S.); Swedish Children's Cancer Foundation (to T.H.); Swedish Pain Relief Foundation (to T.H.). ; Sí

Open Access Article. ; Targeting the hypoxia response pathway and angiogenesis are two promising therapeutic strategies for cancer treatment. Their use as single strategies has important limitations. Thus, development of combined regimens has become an important step toward improving therapeutic efficacy. Also, non-invasive monitoring of the response to targeted biological therapies, as well as determination of the optimal schedule for combination regimens has become an active field of research over the last five years, with relevance for both preclinical and clinical settings. Here, we used an optical imaging method to non-invasively monitor the functional changes in HIF activity in response to antiangiogenic treatment in a xenograft model of human ovarian carcinoma. A bioluminescent reporter construct containing nine copies of the hypoxia response element upstream of the luciferase gene (9xHRE-luciferase) was characterized in vitro in a panel of tumor cell lines and in vivo in a subcutaneous xenograft model of ovarian carcinoma by means of optical imaging. We showed that in OVCAR-3 subcutaneous xenografts, the most abrupt change in the HIF functional reporter occurs before the onset of massive tumor growth. However, this system failed to detect hypoxia induced upon antiangiogenic treatment due to the compensating effects of increased hypoxia and decreased tumor cell viability caused by imbalanced neovascularization vs. tumor expansion. Therefore, the readout based on HIF functional reporter could be conditioned by the dynamics of tumor growth and angiogenesis, which is highly variable depending on the tumor type, tumor model and stage of progression. ; This study was supported by grants from the Ministerio de Ciencia y Tecnología/Ministerio de Ciencia e Innovación (SAF2008-03147 to LdP and SAF2010-19256 to BJ), Comunidad Autónoma de Madrid (S-SAL-0311_2006) and the 7th Research Framework Programme of the European Union (METOXIA, project ref. HEALTH-F2-2009-222741). B.M.P. and V.G. have been supported by a grant from the Comunidad Autónoma de Madrid (S-SAL-0311_2006). ; Peer Reviewed

Bee bread (BB) is a fermented mixture of plant pollen, honey, and bee saliva that worker bees use as food for larvae, and for young bees to produce royal jelly. In the present study, five BB samples, collected from Apis mellifera iberiensis hives located in different apiaries near Bragança, in the northeast region of Portugal, and one BB commercial sample were characterized by high-performance liquid chromatography coupled to a diode array detector and electrospray mass spectrometry (HPLC-DAD-ESI/MS) in terms of phenolic compounds, such as flavonoid glycoside derivatives. Furthermore, the samples were screened, using in vitro assays, against different human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), HeLa (cervical carcinoma) and HepG2 (hepatocellular carcinoma), and also against non-tumor liver cells (porcine liver cells, PLP2). The main phenolic compounds found were flavonol derivatives, mainly quercetin, kaempferol, myricetin, isorhamnetin and herbacetrin glycoside derivatives. Thirty-two compounds were identified in the six BB samples, presenting BB1 and BB3 with the highest contents (6802 and 6480 µg/g extract, respectively) and the highest number of identified compounds. Two isorhamnetin glycoside derivatives, isrohamnetin-O-hexosyl-O-rutinoside and isorhamnetin-O-pentosyl-hexoside, were the most abundant compounds present in BB1; on the other hand, quercetin-3-O-rhamnoside was the most abundant flavonol in BB3. However, it was not possible to establish a correlation between the flavonoids and the observed low to moderate cytotoxicity (ranging from > 400 to 68 µg/mL), in which HeLa and NCI-H460 cell lines were the most susceptible to the inhibition. To the authors' knowledge, this is the first report characterizing glycosidic flavonoids in BB samples, contributing to the chemical knowledge of this less explored bee product. ; The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support to CIMO (Pest-OE/AGR/UI0690/2013) and L. Barros grant (SFRH/BPD/107855/2015). Also, to POCI-01-0145-FEDER-006984 (LA LSRE-LCM), funded by FEDER, through POCI-COMPETE2020 and FCT. The GIP-USAL is financially supported by the Spanish Government through the project AGL2015-64522-C2-2-R. ; info:eu-repo/semantics/publishedVersion

New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

[EN] The induction of senescence produces a stable cell cycle arrest in cancer cells, thereby inhibiting tumor growth; however, the incomplete immune cell-mediated clearance of senescent cells may favor tumor relapse, limiting the long-term anti-tumorigenic effect of such drugs. A combination of senescence induction and the elimination of senescent cells may, therefore, represent an efficient means to inhibit tumor relapse. In this study, we explored the antitumor efficacy of a combinatory senogenic and targeted senolytic therapy in an immunocompetent orthotopic mouse model of the aggressive triple negative breast cancer subtype. Following palbociclib-induced senogenesis and senolysis by treatment with nano-encapsulated senolytic agent navitoclax, we observed inhibited tumor growth, reduced metastases, and a reduction in the systemic toxicity of navitoclax. We believe that this combination treatment approach may have relevance to other senescence-inducing chemotherapeutic drugs and additional tumor types. Significance: While the application of senescence inducers represents a successful treatment strategy in breast cancer patients, some patients still relapse, perhaps due to the subsequent accumulation of senescent cells in the body that can promote tumor recurrence. We now demonstrate that a combination treatment of a senescence inducer and a senolytic nanoparticle selectively eliminates senescent cells, delays tumor growth, and reduces metastases in a mouse model of aggressive breast cancer. Collectively, our results support targeted senolysis as a new therapeutic opportunity to improve outcomes in breast cancer patients. ; The M.O. laboratory members thank the financial support from the Spanish Government (project SAF2017-84689-R (MINECO/AEI/FEDER, EU)) and the Generalitat Valenciana (project PROMETEO/2019/065). The R.M. laboratory members thank the financial support from the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/FEDER, EU) and the Generalitat Valenciana (project ...

[Purpose]: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL. [Experimental Design]: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice. [Results]: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor. [Conclusions]: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. ; Ministerio de Ciencia e Innovación grants SAF2005-04293, SAF2006-8850, SAF2007-61261, SAF2007-60964, PCT-090100-2007-27, PS09/01915, and SAF2008-02251; Red Temática de Investigación Cooperativa en Cáncer grants RD06/0020/0014, RD06/0020/0097, and RD06/0020/1037 (Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union); Fondo de Investigación Sanitaria and European Commission grant FIS-FEDER 06/0813; Junta de Castilla y León (CSI01A08, GR15-Experimental Therapeutics and Translational Oncology Program, and Biomedicine Project 2009); Fundación de Investigación Médica Mutua Madrileña; Fundación "la Caixa" grant BM05-30-0; Caja Navarra Foundation; Department of Health of the Government of Navarra ("Ortiz de Landázuri, 2009" project); and AGAUR-Generalitat de Catalunya grant 2005SGR-00549. C. Gajate is supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain. A. Estella-Hermoso de Mendoza is supported by Department of Education of the Basque Government research grant BFI06.37. M. de Frias is a recipient of a fellowship from the AGAUR-Generalitat de Catalunya. G. Roué holds a Miguel Servet research contract from Instituto de Salud Carlos III. ; Peer Reviewed

Since ancient times, humans have employed different plant species to prepare traditional remedies and treat diseases, due to the health-promoting effects associated with these plants. Among them, several species belonging to the Rosaceae family, namely Agrimonia eupatoria L., Filipendula ulmaria (L.) Maxim. and Rosa canina L., which have been used in different preparations, like infusions, decoctions or tinctures, to treat diverse illnesses and diseases [1]. Nowadays, the search for natural derived ingredients has prompted the study of these traditional plants. The present work aimed to evaluate the biological properties of the above-mentioned Rosaceae species, in order to promote their applications in different sectors. Antioxidant activity was evaluated by different in vitro assays: 2,2-diphenylpycrilhydrazyl (DPPH) radical scavenging assay, thiobarbituric acid reactive substances (TBARS) assay for inhibition of lipid peroxidation, OxHLIA assay for inhibition of oxidative hemolysis, and reducing power determination. Antitumor activity was tested against four tumor cell lines: MCF-7, CaCo, AGS and NCI-H460. Finally, anti-inflammatory activity was assessed by the inhibition of inflammation on lipopolysaccharide-induced RAW264.7 murine macrophages. Considering the results, all plant extracts showed antioxidant effects in the tested assays, especially F. ulmaria. All tested extracts also displayed relevant antitumor effects against the four tested tumor cell lines, mostly F. ulmaria, which exhibited the lowest growth inhibition 50 values (GI50) ranging from 34 to 86 μg/mL of extract, presenting a noteworthy cytotoxic effect. Finally, R. canina showed significant anti-inflammatory effects, with effective concentration 50 values (EC50) of 20 μg/mL of extract. Therefore, the studied plants may be considered as promising natural sources of bioactive compounds with multifunctional biological properties for the development of several biobased applications. ; The research leading to these results was supported by MICINN supporting the Ramón y Cajal grant for M.A. Prieto (RYC-2017-22891) and the Juan de la Cierva Formación grant for T. Oludemi (FJC2019-042549-I), by Xunta de Galicia for supporting the program EXCELENCIA-ED431F 2020/12, the pre-doctoral grant of P. Garcia-Oliveira (ED481A-2019/295) and the program Grupos de Referencia Competitiva (GRUPO AA1-GRC 2018) that supports the work of M. Barral-Martinez. Authors are grateful to Ibero-American Program on Science and Technology (CYTED—AQUA-CIBUS, P317RT0003), to the Bio Based Industries Joint Undertaking (JU) under grant agreement No 888003 UP4HEALTH Project (H2020-BBI-JTI-2019) that supports the work of P. Garcia-Perez. The JU receives support from the European Union's Horizon 2020 research and innovation program and the Bio Based Industries Consortium. The project SYSTEMIC Knowledge hub on Nutrition and Food Security, has received funding from national research funding parties in Belgium (FWO), France (INRA), Germany (BLE), Italy (MIPAAF), Latvia (IZM), Norway (RCN), Portugal (FCT), and Spain (AEI) in a joint action of JPI HDHL, JPI-OCEANS and FACCE-JPI launched in 2019 under the ERA-NET ERA-HDHL (n° 696295). Authors are also grateful to Foundation for Science and Technology (FCT, Portugal) for financial support through national funds FCT/MCTES to the CIMO (UIDB/00690/2020). ; info:eu-repo/semantics/publishedVersion

Yongwei Gu,1,2,* Juanjuan Ma,2,* Zhiqin Fu,1,2,* Youfa Xu,1,2 Baoan Gao,1,2 Jianzhong Yao,3 Wei Xu,1 Kedan Chu,1 Jianming Chen1,2 1Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People's Republic of China; 2Shanghai Wei Er Biopharmaceutical Technology Co., Ltd., Shanghai 201707, People's Republic of China; 3School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China*These authors contributed equally to this workCorrespondence: Wei Xu; Jianming ChenDepartment of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People's Republic of ChinaTel/fax +86-591-22861693; +86-21-31198900-8949Email 2000017@fjtcm.edu.cn; chenjm0711@163.comPurpose: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect.Methods: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3′-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies.Results: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue.Conclusion: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.Keywords: combretastatin A4, liposome, prodrug, drug release, anticancer