Costunosides A-C: cytotoxic sesquiterpene lactones from the rhizomes of Aucklandia costus Falc.

Three new eudesmane type rare sesquiterpene lactone galactosides, costunosides A-C (1-3) were isolated from the rhizomes of Aucklandia costus along with ten known compounds (4-13). Costunosides A-C (1-3) are the first example of naturally eudesmane glycosides containing a ß-galactopyranoside moiety. The structure and relative configurations of these compounds were established by comprehensive analysis of MS and, in particular 1D/2D NMR spectroscopic data. The isolated compounds were tested against a panel of human cancer cell lines, where compounds 3, 6 and 7 have shown promising cytotoxic activity against PC-3, HCT-116 and A549 cell lines with IC50 values in the range of 3.4 µM to 9.3 µM, respectively. Costunosides A-C (1-3) were also screened for inhibition assay of acetyl-cholinesterase (AChE), and butyrylcholinesterase (BChE) and found inactive at a concentration of 10 µM.

Apoptotic Potential and Antitumor Efficacy of Trilliumoside A: A New Steroidal Saponin Isolated from Rhizomes of Trillium govanianum.

Natural product-derived molecules exhibit potential as anticancer agents. Trilliumoside A, a new steroidal saponin, was obtained from rhizomes of Trillium govanianum, and its anticancer activity was investigated in the presented study. Trilliumoside A was investigated in a panel of cell lines, and it exhibited promising cytotoxic activity on the A549 cells (human lung cancer cells) with an IC50 of 1.83 µM. The mechanism of cell death induced by Trilliumoside A in A549 cells and its anticancer potential in murine tumor models (EAC and EAT) were presented in the current research. Trilliumoside A was found to induce apoptosis in A549 cells by increasing the expression of various apoptotic proteins, such as Bax, Puma, cytochrome C, cleaved PARP, and cleaved caspase 3. Additionally, Trilliumoside A regulates the expression of p53, CDK2, and Cyclin A by decreasing the mitochondrial membrane potential, elevating reactive oxygen species, and stopping the growth of A549 cells in the synthesis phase (S) of the cell cycle. Trilliumoside A showed a considerable reduction in the tumor volume, the amount of ascitic fluid, and the total cell number without affecting the body weight of animals. Our results demonstrate that Trilliumoside A inhibits the proliferation of human lung cancer cells by inducing DNA damage, arresting the cell cycle, and activating the mitochondrial signaling pathway. The study demonstrated the potential of Trilliumoside A as a potential anticancer agent.

Antifibrotic Agent Mediated Tumor Microenvironment Modulation and Improved Nanomedicine Delivery in Solid Tumor.

The unique physiology of tumors limits the efficacy of chemotherapeutics. In efforts to improve the effectiveness of the existing chemotherapy drugs, nanomedicine emerged as a new hope but proved inadequate due to the transport barriers present within the tumor tissues, which limits the potential of nanomedicine. Dense collagen networks in fibrotic tissues contribute to hindering the penetration of molecular- or nano-scale medicine through tumor interstitium. In the present study, human serum albumin (HSA)-based nanoparticles (NPs) were developed for gemcitabine (GEM) and losartan (LST), which could offer secreted protein acids rich in cysteine (SPARC) and enhanced permeability and retention effect (EPR)-mediated drug accumulation in tumors. Also, the tumor microenvironment (TME) modulation approach using LST was coupled to investigate the impact on antitumor efficacy. GEM-HSA NPs and LST-HSA NPs were prepared by the desolvation-cross-linking method and characterized for size, potential, morphology, drug loading, drug-polymer interactions, and hemocompatibility. For investigating the efficacy of prepared NPs, cytotoxicity and mechanisms of cell death were elucidated in vitro by using various assays. Intracellular uptake studies of prepared HSA NPs indicated their uptake and cytoplasmic localization. Furthermore, in vivo studies demonstrated significantly improved anticancer efficacy of GEM-HSA NPs in combination with LST pretreatment. Extended LST treatment further improved the anticancer potential. It was shown that the improved efficacy of the nanomedicine was correlated with the reduced thrombospondin-1 (TSP-1) and collagen level in tumor tissue upon LST pretreatment. Moreover, this approach exhibited augmented nanomedicine accumulation in the tumor, and hematological, biochemical, and tissue histology indicated the safety profile of this combination regimen. Concisely, the undertaken study demonstrated the potential of the triple targeting (SPARC, EPR, TME modulation) approach for augmented efficacy of chemotherapeutics.

In vitro and in vivo anticancer potential and molecular targets of the new colchicine analog IIIM-067.

OBJECTIVE: The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells. METHODS: Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice. RESULTS: IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 µmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 µmol/L to 82.1% at 0.4 µmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 µmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 µmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively. CONCLUSION: IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.

Gold nanoblackbodies mediated plasmonic photothermal cancer therapy for melanoma.

Aim: Gold nanoblackbodies (AuNBs)-mediated plasmonic photothermal cancer therapy was investigated through melanoma-bearing mice. Materials & methods: Polydopamine-coated Au nanoclusters were synthesized, termed AuNBs and PEGylated AuNBs (AuNBs-PEG). The photothermal response of AuNBs-PEG was evaluated upon low-intensity broadband near-infrared irradiation (785/62 nm; 0.9 Wcm-2), and cytotoxicity was assessed on B16-F10 cells. Further, the therapeutic potential of intravenously administered AuNBs-PEG was evaluated on B16-F10 melanoma in C57BL/6 mice. Results: AuNBs-PEG showed an excellent photothermal response (photothermal conversion efficiency of 60.3%), robust photothermal stability and no cytotoxicity. For AuNB-mediated plasmonic photothermal therapy, an average temperature of 63°C was attained within 5 min of irradiation, and tumors were eradicated. Conclusion: AuNBs-PEG are promising photothermal agents for treating melanoma through low-intensity broadband near-infrared irradiation.

Implication of methylselenocysteine in combination chemotherapy with gemcitabine for improved anticancer efficacy.

The limitations associated with cancer monotherapy including dose dependent toxicity and drug resistance can be addressed by combination chemotherapy. The combination of antineoplastic agents improves the cytotoxic activity in comparison to the single-agent based therapy in a synergistic or an additive mode by reducing tumor growth as well as metastatic ability. In the present investigation, we explored the potential of methylselenocysteine (MSC) in combination chemotherapy with gemcitabine (GEM). The cytotoxic activity of GEM and MSC was determined in various cell lines and based on the activity, A549 cells were explored for the mechanistic studies including DAPI staining, measurement of oxidative stress, mitochondrial membrane potential loss, nitric oxide level, western blotting, cell migration and colony formation assays. A549 cells in combination treatment with MSC and GEM demonstrated enhanced cytotoxicity with more irregular cellular morphology as well as chromatin condensation and nuclear blebbing. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, and alleviated cell migration potential and clonogenic propensity of A549 cells. Also, caspase-3 and PARP mediated apoptosis was observed in the combination treated cells. MSC based drug combination could offer the attributes of improved drug delivery and there was a 6-folds dose reduction of GEM in combination. Further, antitumor study in Ehrlich solid tumor model showed the efficacy of MSC combination with GEM for the enhanced antitumor activity. The proposed combination demonstrated the potential for further translational studies.

Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.

Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis. So it is therefore imperative to identify cytotoxic agents that exploit non-apoptotic mechanisms of cell death. Our study showed that pancreatic cancer cells treated with SDS-203 triggered an incomplete autophagic response and a nuclear translocation of transcriptional factor TFEB. This resulted in abundant biosynthesis and accumulation of autophagosomes and lysosomes into the cells leading to their death. It was observed that the silencing of autophagy genes didn't alter the cell fate, whereas siRNA-mediated silencing of TFEB subdued SDS-203 mediated lysosomal biogenesis and associated cell death. Further mouse tumors treated with SDS-203 showed a significant reduction in tumor burden and increased expression of lysosomal markers. Taken together this study demonstrates that SDS-203 treatment triggers non-apoptotic cell death in pancreatic cancer cells through a mechanism of lysosome over accumulation.

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.

An improved synthesis of indanocine and antiproliferative activity of 2-benzylindanocine via microtubule destabilization.

Indanocine, a potent anticancer investigational drug of National Cancer Institute-USA, has been much discussed in recent years. Present communication aimed at total synthesis of indanocine and its close analogues. Total synthesis was improved by double yields than previously reported yields. Some of the benzylidene and 2-benzyl derivatives with free rotation at C2 position exhibited potential cytotoxicities against various human cancer cell lines. Five such analogues exhibited potential antiproliferative effect against HCT-116 and MIA PACA-2 cell lines. Benzylindanocine 12i induced microtubule destabilization by occupying colchicine binding pocket of ß-tubulin. It also exhibited anti-inflammatory activity by down-regulating IL-6 and TNF-α. In Ehrlich ascites carcinoma model, 12i reduced 78.4% of EAC tumour in Swiss albino mice at 90 mg/kg (i.p.) dose. Further, in in vivo safety studies, 12i was found to be safe to rodents up to 1,000 mg/kg dose. Concomitant anticancer and anti-inflammatory activity of benzylindanocine is distinctive, which suggests its further optimization for better efficacy and druggability.

Novel Vitamin E TPGS based docetaxel nanovesicle formulation for its safe and effective parenteral delivery: Toxicological, pharmacokinetic and pharmacodynamic evaluation.

Docetaxel (DTX) is a highly lipophilic, BCS class IV drug with poor aqueous solubility (12.7 µg/mL). Presently, only injectable formulation is available in the market which uses a large amount of surfactant (Tween 80) and dehydrated alcohol as a solubilizer. High concentrations of Tween 80 in injectable formulations are associated with severe consequences i.e. nephrotoxicity, fluid retention, and hypersensitivity reactions. The present study aims to eliminate Tween 80, thus novel biocompatible surfactant Vitamin E TPGS based nanovesicle formulation of DTX (20 mg/mL) was developed and evaluated for different quality control parameters. Optimized nanovesicular formulation (NV-TPGS-3) showed nanometric size (102.9 ± 2.9 nm), spherical vesicular shape, high drug encapsulation efficiency (95.2 ± 0.5%), sustained-release profile and high dilution integrity with normal saline. In vitro cytotoxicity assay, showed threefold elevation in the IC50 value of the optimized formulation in comparison to the commercial formulation. Further, no mortality and toxicity were observed during 28 days repeated dose sub-acute toxicity studies in Swiss albino mice up to the dose of 138 mg/kg, whereas, commercial formulation showed toxicity at 40 mg/kg. In addition, in vivo anticancer activity on Ehrlich Ascites Carcinoma induced mice showed a significant tumour growth inhibition of 76.3 ± 5.3% with the NV-TPGS-3 treatment when compared to Ehrlich Ascites Carcinoma control. Results demonstrated that the developed Vitamin E TPGS based nanovesicular formulation of DTX could be a better alternative to increase its clinical uses with improved therapeutic efficacy, reduced toxicity and dosing frequency, and sustained drug release behaviour.

Binary and ternary solid dispersions of an anticancer preclinical lead, IIIM-290: In vitro and in vivo studies.

The objective of this study was to formulate an anticancer preclinical lead, IIIM-290, loaded in solid dispersions to enhance its solubility, dissolution, and oral pharmacokinetics. IIIM-290 is an in-house preclinical anticancer lead prepared by semisynthetic modification of the natural product rohitukine. It is an orally bioavailable Cdk inhibitor showing efficacy in xenograft models of pancreatic, colon and leukemia cancer. It demonstrated in vivo efficacy at a relatively higher dose owing to its poor aqueous solubility (~8.6 µg/mL). Binary and ternary solid dispersions containing PVP K-30, xanthan gum, and PEG-PPG-PEG were selected after solubility screening of various hydrophilic polymers. Several formulations with varying ratios of polymers, alone and in combination, were prepared and investigated for their effects on the solubility enhancement of IIIM-290. The binary solid dispersion VKB-SD75, prepared with PVP K-30 at the ratio of 1:4 w/w, was identified as the optimized composition that displayed 17-fold improvement in the aqueous solubility of IIIM-290. VKB-SD75 was scaled up to a 100-g scale. IIIM-290 and VKB-SD75 were evaluated for DSC, p-XRD, FTIR, 1H NMR, SEM, in vitro dissolution, and oral pharmacokinetics, as well as for in vivo anticancer activity in the Ehrlich solid tumor model. The oral administration of VKB-SD75 in BALB/c mice resulted in a 1.9-fold improvement in plasma exposure. These findings also correlated well when the formulation was administered to mice in the Ehrlich solid tumor model. The newly developed solid dispersion is expected to reduce the dose of IIIM-290 by ~40-50% in preclinical and clinical studies.

Gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for improved efficacy of cancer chemotherapy.

The present study demonstrated the development of gemcitabine and betulinic acid co-encapsulated PLGA-PEG polymer nanoparticles for enhancing the chemotherapeutic response. This combinatorial PLGA-PEG nanoparticle was formulated using double emulsion and had size <200 nm. The developed nanoparticles were characterized using dynamic light scattering and transmission electron microscopy for their size and shape, respectively. The in vitro release of the drugs from combinatorial nanoparticles was predominantly followed by Fickian diffusion phenomenon. Study on hemocompatibilty approved the administration of this combinatorial nanoparticle for animal study. In vitro cytotoxicity study on Panc1 cells using MTT assay, reactive oxygen species production and cellular apoptotic assay demonstrated that combinatorial nanoparticle was more cytotoxic compared to native drugs solution. Furthermore, the combinatorial nanoparticle suppressed tumor growth more efficiently in Ehrlich (solid) tumor model than the native gemcitabine and betulinic acid at the same concentrations. These findings indicated that PLGA-PEG nanoparticle might be used to co-deliver multiple chemotherapeutic drugs with different properties for enhancing antitumor efficacy.

Synthesis and Investigation of the Role of Benzopyran Dihydropyrimidinone Hybrids in Cell Proliferation, Migration and Tumor Growth.

BACKGROUND: Cancer is the second leading cause of mortality worldwide after heart diseases, and lung cancer is the topmost cause of all cancer-related deaths in both sexes. Dihydropyrimidinones (DHPMs) are medicinally important class of molecules with diverse pharmacological activities including anticancer activity. The present study focuses on the molecular hybridization of novel Benzopyran with Dihydropyrimidinone and evaluation of the resulting hybrids for cancer cell proliferation, migration and tumor growth. METHODS: We have synthesized a focused library of dihydropyrimidinone benzopyran hybrids (compounds 1-11) by joining the aromatic as well as pyran portions of the benzopyran core with dihydropyrimidinone. All the synthesized hybrid molecules were evaluated for their cytotoxic activities against a panel of four human cancer cell lines of diverse tissue origin, viz: A549 (lung carcinoma), MCF7 (mammary gland adenocarcinoma), HCT-116 (colorectal carcinoma), and PANC-1 (pancreatic duct carcinoma) with the help of MTT cell viability assay. A structure-activity relationship was made on the basis of IC50 values of different hybrids. Effect on cell proliferation was examined through colony formation assay, reactive oxygen species generation and mitochondrial membrane potential studies. Wound healing assays and cell scattering assays were employed to check the effect on cell migration. Western blotting experiments were performed to find out the molecular mechanism of action and anti-tumor studies were carried out to evaluate the in vivo efficacy of the selected lead molecule. RESULTS: Two types of novel hybrids were synthesized efficiently from benzopyran aldehydes, ethylacetoacetate and urea under heteropolyacid catalysis. Compound 3 was found to be the most potent hybrid among the synthesized compounds with consistent cytotoxic activities against four human cancer cell lines (IC50 values: 0.139 - 2.32 µM). Compound 3 strongly inhibited proliferation abilities of A549 cells in colony formation assay. Compound 3 exerted oxidative stress-mediated mitochondrial dysfunction, in which mitochondrial reactive oxygen species (ROS) generation as a mechanism of its anti-proliferative effects was analysed. Further, the molecule abrogated migration and cell scattering properties of aggressive PANC-1 cells. Mechanistic studies revealed that compound 3 modulated NF-kB expression and its downstream oncogenic proteins involved in cancer cell proliferation and invasion. Finally, compound 3 confirmed its in vivo anti-tumor efficacy; there observed 41.87% tumor growth inhibition at a dose of 30 mg/kg/body weight against a mouse model of Ehrlich solid tumor. CONCLUSION: Our study unravels a potential anticancer lead (compound 3) from DHPMs that have opened up new research avenues for the development of promising anticancer therapeutic agents.

Antitumour, acute toxicity and molecular modeling studies of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H)-one against Ehrlich ascites carcinoma and sarcoma-180.

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 µM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (EAT, solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile since all 51 computed physicochemical parameters fall within the recommended range for 95% of known drugs. The current study provides insight for further investigation of the antitumour potential of the molecule.

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor.

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 µM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.

4-aryl/heteroaryl-4H-fused Pyrans as Anti-proliferative Agents: Design, Synthesis and Biological Evaluation.

AIMS: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines. DESCRIPTION: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds. Compound FP-(v)n displayed noteworthy cytotoxicity towards HCT-116 malignant cells with the IC50 value of 0.67 µM. It induces apoptosis as revealed by several biological endpoints like apoptotic body formation, through DAPI staining, phase contrast microscopy and mitochondrial membrane potential loss. Moreover FP-(v)n is a potent apoptotic inducer confirmed by cell cycle arrest and ROS generation. The cell phase distribution studies indicate an augment from 4.94 % (control sample) to 39.68 % (sample treated with 1.5 µM compound FP-(v)n) in the apoptotic population. Compound FP-(v)n inhibits the tumor growth in Ehrlich ascites carcinoma (EAC), Ehrlich Tumor (ET, solid) and sarcoma-180 (solid) mice models. Additionally, it was established to be non-toxic at maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. CONCLUSION: The current study provides an insight into anti-cancer potential of FP-(v)n, which might be valuable in the treatment of tumor.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Development and characterization of hyaluronic acid modified PLGA based nanoparticles for improved efficacy of cisplatin in solid tumor.

Cisplatin is a potent and widely used chemotherapeutic agent to treat a variety of tumors. However, its clinical use is associated with undesirable side effects and acquired resistance to cisplatin. In this study, cisplatin loaded hyaluronic acid (HA) functionalized poly (lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles (CP-HA-PLGA-PEG-NPs) were fabricated using double emulsion solvent evaporation method to target CD44 receptor expressed on cancerous cells. The developed nanoconstructs were characterized for various in vitro parameters, including size distribution, zeta potential, morphology, drug loading and in vitro release. The HA content on the HA-PLGA-PEG-NPs was quantified by a turbidimetric method. The in vitro anticancer study in human ovarian cancer (SKOV-3) cells showed significantly (p<0.05) higher cytotoxicity of CP-HA-PLGA-PEG NPs as compared to free cisplatin and non-targeted nanoparticles (CP-PLGA-PEG NPs). Further, laser scanning confocal microscopy revealed that there was enhanced cellular uptake of HA-PLGA-PEG NPs in CD44-over expressing ovarian cancer cell line (SKOV-3). The in vivo antitumor activity of CP-HA-PLGA-PEG-NPs was significantly (p<0.05) higher than free cisplatin and CP-PLGA-PEG-NPs in Ehrlich tumor (solid) bearing mice. The results demonstrated the potential of target specific nanoconstruct of cisplatin in the improved cancer chemotherapy.

Development and evaluation of long-circulating nanoparticles loaded with betulinic acid for improved anti-tumor efficacy.

The clinical application of betulinic acid (BA), a natural pentacyclic triterpenoid with promising antitumor activity, is hampered due to its extremely poor water solubility and relatively short half-life in the systemic circulation. In order to address these issues, herein, we developed betulinic acid loaded polylactide-co-glycolide- monomethoxy polyethylene glycol nanoparticles (PLGA-mPEG NPs). The PLGA-mPEG co-polymer was synthesized and characterized using NMR and FT-IR. BA loaded PLGA-mPEG NPs were prepared by an emulsion solvent evaporation method. The developed nanoparticles had a desirable particle size (∼147nm) and exhibited uniform spherical shape under transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The PLGA-mPEG NPs were able to decrease the uptake by macrophages (i.e. J774A.1 and Raw 264.7 cells) as compared to PLGA nanoparticles. In vitro cytotoxicity in MCF7 and PANC-1 cells demonstrated enhanced cytotoxicity of BA loaded PLGA-mPEG NPs as compared to free BA. The cellular uptake study in both the cell lines demonstrated time dependent uptake behavior. The enhanced cytotoxicity of BA NPs was also supported by increased cellular apoptosis, mitochondrial membrane potential loss, generation of high reactive oxygen species (ROS) and cell cycle arrest. Further, intravenous pharmacokinetics study revealed that BA loaded PLGA-mPEG NPs could prolong the circulation of BA and remarkably enhance half-life by ∼7.21 folds. Consequently, in vivo studies in Ehrlich tumor (solid) model following intravenous administration demonstrated superior antitumor efficacy of BA NPs as compared to native BA. Moreover, BA NPs treated Ehrlich tumor mice demonstrated no biochemical, hematological and histological toxicities. These findings collectively indicated that the BA loaded PLGA-mPEG NPs might serve as a promising nanocarrier for improved therapeutic efficacy of betulinic acid.