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o‐Aminoazotoluene (OAT), capable of photoisomerization, and o‐vanillin, a potent comutagen, have been used to synthesize a new ligand, HL, [C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OH)(OCH3)], which, upon complexation with copper(II), results in a new copper(II) complex‐Cu(L)2, [Cu{C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OCH3)O}2]. Both HL and Cu(L)2 have been characterized by single‐crystal X‐ray diffraction measurements along with other analytical techniques, for example, IR spectroscopy, NMR spectroscopy, UV–Vis spectroscopy, elemental analysis and mass spectrometry. These compounds were tested with different in vitro anticancer assay as well as with in silico studies. A comparative study has been demonstrated on anticancer activity of HL and Cu(L)2 with the ligand HAZ, {C6H5N=NC6H4N=CHC6H3(OH)(OCH3)} and its Cu‐complex, [Cu(AZ)2, Cu{C6H5N=NC6H4N=CHC6H3(OCH3)O}2]. The sensing properties of HAZ, along with the synthesis and structural properties of both HAZ and Cu(AZ)2, have been reported by our group earlier. Cytotoxicity measurements on MCF7 cell lines show that Cu(L)2 and Cu(AZ)2 have higher anticancer activity than their corresponding ligands. The apoptotic effect of Cu‐complex was studied through nuclear fragmentation assay and AO/EB dual‐staining assay on MCF7 cell line. The IC50 value of Cu(L)2 in 0.01% DMSO/water after 24‐h treatment was found 4.2 μM, which is one of the lowest values with this response time compared to the other analogous anticancer compounds. Finally, we have evaluated the expression of hERα protein with respect to Cu‐complexes, and it was observed that Cu(L)2 caused more down‐regulation of hERα as compared to Cu(AZ)2. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM), an endothelial cell–independent alternative mechanism of blood supply to the malignant tumour, has long been considered as an adverse prognostic factor in many cancers. The correlation of VM with laminin‐5γ2 and the assessment of their harmonized expression as an independent risk factor have not been elucidated yet in oral squamous cell carcinoma (OSCC). CD31/PAS staining stratified 116 clinically diagnosed OSCC specimens into VM+ and VM− cohorts. The expression pattern of laminin‐5γ2 and its upstream modulator MMP2 was evaluated by immunohistochemistry and Western blot. The Kaplan–Meier and Cox regression analyses were performed to assess the survival and prognostic implications. The presence of VM demonstrated a significant correlation with the expression of laminin‐5γ2 (p <.001) and MMP2 (p <.001). This pattern was mirrored by the significant upregulation of laminin‐5γ2 and MMP2 in VM+ cohorts compared with the VM− ones. Furthermore, co‐expression of VM and laminin‐5γ2 was significantly associated with tumour grade (p =.010), primary tumour size (p <.001), lymph node metastasis (p =.001) and TNM stages (p <.001) but not with patients' age, gender, tobacco and alcohol consumption habit. Vasculogenic mimicry and laminin‐5γ2 double‐positive cohort displayed a significantly poorer disease‐free survival (DFS) and overall survival (OS). Vasculogenic mimicry, laminin‐5γ2 and their subsequent dual expression underlie a significant prognostic value for DFS [hazard ratio (HR) = 9.896, p =.028] and OS [HR = 21.401, p =.033] in OSCC patients. Together, our findings imply that VM along with laminin‐5γ2 is strongly linked to the malignant progression in OSCC and VM and laminin‐5γ2 coordination emerges as a critical prognostic biomarker for OSCC. [ABSTRACT FROM AUTHOR]

Abstract Vasculogenic mimicry, an endothelia-independent tumor microcirculation has been found in various cancers and is thought to be achieved by cancer stem like cells. Dacarbazine resistance is one of the most common features of melanoma and recent studies suggest that the mode of resistance is closely related to the formation of vasculogenic mimicry. In our work, we examined the anticancer effect of Lupeol, a novel phytochemical with Dacarbazine in vivo and in vitro. Results demonstrated adequate cytotoxicity followed by down regulation of CD 133 expression in Lupeol treated B16-F10 cell line. In solid tumor model the drug also inhibited vasculogenic mimicry along with angiogenesis by altering both the cancer stem cell as well as the endothelial progenitor cell population. Lupeol hindered the maturation of bone marrow derived endothelial progenitors and thus, retarded the formation of rudimentary tumor microvessels. Notably, Dacarbazine treatment demonstrated unresponsiveness to B16-F10 cells in both in vivo and in vitro model via upregulation of CD 133 expression and increased formation of vasculogenic mimicry tubes. Together, these data indicate that Lupeol alone can become a proficient agent in treating melanoma, inhibiting vasculogenic mimicry and might play a significant role in subduing Dacarbazine induced drug resistance. Highlights • Lupeol shows excellent cytotoxicity against B16-F10 melanoma cancer cells in vivo and in vitro. • Lupeol overcomes Dacarbazine resistance by inhibiting vasculogenic mimicry. • Lupeol also inhibits tumor angiogenesis by inhibiting the maturation and homing of Endothelial Progenitor Cells (EPC). [ABSTRACT FROM AUTHOR]

A new coumarin based fluorescent switch PCEH is fabricated which displays high selective sensing towards Al3+ among other metal cations at physiological pH. On gradual addition of Al3+, PCEH shows a brilliant "turn-on" emission enhancement in MeOH/H2O (4/1, v/v) solution. This new fluorescent switch is proven to be a reversible probe by gradual addition of F− into the PCEH-Al3+ solution. Detection limit as well as binding constant values are calculated to be in the order of 10–9 M and 104 M−1 respectively. We have also explored its potential as a biomarker in the application of live cell imaging using breast cancer cells (MDA-MB-231 cell). [ABSTRACT FROM AUTHOR]

A highly sensitive, reversible, reusable and fluorogenic "turn-on" probe (HBTC) is fabricated for the sole detection of Al3+. On incremental addition of Al3+ in a solution of HBTC in ACN : H2O (4 : 1), a sharp "turn-on" emission enhancement is observed at 480 nm. The reversibility of the probe (HBTC) was displayed on the addition of F− solution. The detection limit is found to be of the order of 10−9 M which suggests that HBTC can detect Al3+ at a very minute level. The mechanism for Al3+ detection in ACN : H2O (4 : 1) is attributed to forbidding C＝N isomerization and ESIPT process simultaneously turning on the chelation-enhanced fluorescence process. The reusability and real-time application of the probe are also studied. Bioimaging study reveals that HBTC can detect Al3+ in human breast cancer cells (MDA-MB-231). Electronic structure of the probe is explained by density functional theory. [ABSTRACT FROM AUTHOR]

Background: Despite our efforts to develop effective treatment paradigms, the overall success rates of most of the anti-cancer therapies for aggressive cancers remain very low. There is an urgent need to develop novel therapeutics to meet the present challenges. In recent years, several plant derived chemicals showed promising return as antineoplastic agents. Objective: Here, we evaluate the anticancer effects of one well known phytochemical Lupeol on a panel of aggressive cancer types in preclinical platforms. Methods: Melanoma (B16- F10), breast cancer (MDA MB- 231), Cisplatin resistant laryngeal cancer cell line HEp-2c, oral cancer cell line UPCI: SCC131 and prostate cancer (PC-3) cell lines were treated with different doses of Lupeol for 24 and 48 hours. Cytotoxic effects of these agents were measured by different endpoint assays. Matrigel tube formation, Limiting Dilution (LD) and sphere formation assay along with alteration in CD133 expression were performed. The expression status of Ephrin A2 and its downstream molecules were examined in aggressive mouse melanoma solid tumor in vivo. We also established the key findings in a patient derived ex vivo explant model (CANScript TM) for human breast and HNSCC tumors. Results: Viability (MTT) assay showed significant IC50 value for each cell lines treated with Lupeol followed by CFU assay. Concurrently, induction of apoptosis was found to be prominent in treatment arm. We also observed down regulation of CD133 expression and disrupted tube formation in all cell lines that together ascertain their ability to inhibit vasculogenic mimicry (VM). The ability of Lupeol to interfere with cancer stem cell (CSC) like properties was also evident where sphere formation and LD profile demonstrated alteration in the CSC pools for majority. The machinery of these effects suggested its link with Ephrin A2 and its downstream elements driving VM in melanoma in vivo tumour model. Further validation of these data in patient derived CANScript ex vivo setting where efficacy of this drug was tested on the patient tumors clinically progressed on standard of care (SOC). Discussion and conclusion: Together, these data suggest the promising roles of phytochemical in treating diverse cancer indications at aggressive or late stages of the diseases where existing paradigms frequently show limited efficacy. [ABSTRACT FROM AUTHOR]

Background: Despite our efforts to develop effective treatment paradigms, the overall success rates of most of the anti-cancer therapies for aggressive cancers remain very low. There is an urgent need to develop novel therapeutics to meet the present challenges. In recent years, several plant derived chemicals showed promising return as antineoplastic agents. Objective: Here, we evaluate the anti-cancer effects of one well known phytochemical Lupeol on a panel of aggressive cancer types in preclinical platforms. Methods: Melanoma (B16- F10), breast cancer (MDA MB- 231), Cisplatin resistant laryngeal cancer cell line HEp-2c, oral cancer cell line UPCI: SCC131 and prostate cancer (PC-3) cell lines were treated with different doses of Lupeol for 24 and 48 hours. Cytotoxic effects of these agents were measured by different endpoint assays. Matrigel tube formation, Limiting Dilution (LD) and sphere formation assay along with alteration in CD133 expression were performed. The expression status of Ephrin A2 and its downstream molecules were examined in aggressive mouse melanoma solid tumor in vivo. We also established the key findings in a patient derived ex vivo explant model (CANScript TM) for human breast and HNSCC tumors. Results: Viability (MTT) assay showed significant IC50 value for each cell lines treated with Lupeol followed by CFU assay. Concurrently, induction of apoptosis was found to be prominent in treatment arm. We also observed down regulation of CD133 expression and disrupted tube formation in all cell lines that together ascertain their ability to inhibit vasculogenic mimicry (VM). The ability of Lupeol to interfere with cancer stem cell (CSC) like properties was also evident where sphere formation and LD profile demonstrated alteration in the CSC pools for majority. The machinery of these effects suggested its link with Ephrin A2 and its downstream elements driving VM in melanoma in vivo tumour model. Further validation of these data in patient derived CANScript ex vivo setting where efficacy of this drug was tested on the patient tumors clinically progressed on standard of care (SOC). Discussion and conclusion: Together, these data suggest the promising roles of phytochemical in treating diverse cancer indications at aggressive or late stages of the diseases where existing paradigms frequently show limited efficacy. [ABSTRACT FROM AUTHOR]

Basis: Our learning from the limited trajectory of biomarker guided and genomic assay based response prediction to inform clinical action ability of cancers led to the strategic rethinking of developing and validating robust and individualized platform (CANScript) that make prediction based on multiple phenotypic inputs. Methods: Accelerated CANScript Enabled Personalized Treatment (ACCEPT) is an investigator initiated study aiming to predict response to anticancer drugs at clinic. Surgically resected tumors from primary breast cancer patients (n=30) were cultured in slices and treated with Epirubicin, Cyclophosphamide and 5FU in CANScript platform for three days in presence of autologous growth factors, immune milieu and indication specific matrix support where patient tumor microenvironment was extensively preserved. The outcome was measured by integrating both pathological (tumor content, viability, proliferation and induction of apoptosis) and kinetic endpoints (cell viability and metabolism) into a single data trained M score algorithm as described (Majumder B et al., Nature Commun, 2015, Brijwani N et al., Scientific Reports, 2017). After 6 cycles of therapy, following surgery, patients were clinically evaluated for response based on multiple criteria including radiological examination. This short-term clinical response was compared with CANScript driven response prediction. Results: Out of 25 evaluable patients, outcome is available for ten patients (40%) till today. Data indicate that CANScript derived predictive scores for responders and non-responders were highly correlated with clinical observation. For all six clinical non-responders, CANScript guided outcome was found to be matched with clinical outcome. Similarly, for rest 4 patients, while CANScript predicted response, 3 patients showed clinical response. These preliminary data from an ongoing study are encouraging and more patients will be enrolled and follow up data will be collected. Conclusion: Phenotypic assay based platform technologies are emerging as a new frontier of individual response prediction based on the complex and dynamic interplay of tumor and stroma including immune network. CANScript guided prediction of response showed encouraging results to understand the response of drugs at clinic, would offer further opportunity to incorporate phenotypic inputs for informed treatment decision in an adjuvant setting. [ABSTRACT FROM AUTHOR]

A phenylazo appended ortho‐vanillin Schiff base scaffold (HAZ) has been used for selective colorimetric sensing of Cu2+ in semi‐aqueous medium (methanol–water, 1:1, v/v) in the presence of 16 cations and 20 anions, and the limit of detection is 1.8 × 10−7 M. The structures of HAZ and Cu (II) complex, [Cu(AZ)2], have been characterised by spectroscopic data (UV–Vis, Fourier transform infrared and electron paramagnetic resonance) and established by the single crystal X‐ray diffraction measurement. The Job's plot from the absorption studies has also confirmed the 1:2 stoichiometry of Cu2+:HAZ. The absorption spectrum of [Cu (AZ)2] has returned to the spectrum of HAZ on the addition of Na2EDTA solution which is again recovered upon the addition of Cu2+ solution. Discrete Fourier transform computations were carried out using the coordinates of the X‐ray structures of the compounds, and the molecular functions were used to correlate the solution spectroscopic properties. In addition to this, the probe is treated on MDA‐MB 231 breast cancer cells to check the cytotoxicity. The probe is used for the detection of trace quantity of Cu2+ in the cancer cell. [ABSTRACT FROM AUTHOR]

Hypericum roeperianum is a medicinal spice traditionally used in West Africa to treat female sterility, fungal infections, and cancer. It has previously been reported that H. roeperianum exhibits cytotoxic potential by reducing the viability of cancer cells involving multidrug-resistant phenotypes, but its underlying molecular mechanism remains unknown. The mechanistic involvement of H. roeperianum methanolic crude extract (HRC) in attenuating breast cancer progression by exploring the effects on mitochondrial apoptosis and epithelial-mesenchymal transition (EMT) was investigated. In the present study, we examined the anticancer properties of HRC through MTT assay, colony formation, wound healing assay, spheroid formation, DNA fragmentation and flow cytometry for cell cycle arrest, apoptosis (Annexin V/PI staining) and mitochondrial membrane potential (MMP) (JC-1) detection. In addition, western blot analysis of various proteins and quantitative real time PCR of various genes involved in apoptosis, EMT and the PI3K/Akt/mToR signal transduction pathway were performed. This study revealed that HRC treatment significantly decreased breast cancer cell viability, colony forming efficiency and reduced the ability of cell migration and spheroid formation. HRC also induced apoptosis in MDA-MB-231 and MCF-7 via promoting G0/G1 cell cycle arrest, disruption of mitochondrial membrane potential and induction of DNA damage. The crude extract induced apoptosis by activating the intrinsic pathway with a stronger effect that relies on the combined potency of associated molecular markers including Bax, Bad, Bcl-2, cytochrome C, caspase-9, and cleaved-PARP. It was also found that HRC regulates the PI3K/Akt/mToR pathway. In addition, HRC inhibited EMT by expressional alteration of Vimentin and E-cadherin, as well as the regulatory transcription factors such as Snail and Slug. The in vitro findings reflected similar mechanistic approach in 4T1 cell induced syngeneic mice model, indicating the reduction of tumor volume along with the significant expressional alteration of EMT and apoptotic markers. Taken together the findings concluded that H. roeperianum is a potential source of cytotoxic phytochemicals that exhibit abortifacient effect on breast cancer, both in vitro and in vivo , thus could further be utilized in breast cancer therapy. [Display omitted] • The anticancer mechanism of action of Hypericum roeperianum crude extract (HRC) was evaluated. • HRC also induced apoptosis in MDA-MB-231 and MCF-7. • HRC causes G0/G1 cell cycle arrest, disruption of mitochondrial membrane potential and DNA damage. • HRC inhibited the epithelial-mesenchymal transition. [ABSTRACT FROM AUTHOR]

Basis: Our learning from the limited trajectory of biomarker guided and genomic assay based response prediction to inform clinical action ability of cancers led to the strategic rethinking of developing and validating robust and individualized platform (CANScript) that make prediction based on multiple phenotypic inputs. Methods: Accelerated CANScript Enabled Personalized Treatment (ACCEPT) is an investigator initiated study aiming to predict response to anticancer drugs at clinic. Surgically resected tumors from primary breast cancer patients (n=30) were cultured in slices and treated with Epirubicin, Cyclophosphamide and 5FU in CANScript platform for three days in presence of autologous growth factors, immune milieu and indication specific matrix support where patient tumor microenvironment was extensively preserved. The outcome was measured by integrating both pathological (tumor content, viability, proliferation and induction of apoptosis) and kinetic endpoints (cell viability and metabolism) into a single data trained M score algorithm as described (Majumder B et al., Nature Commun, 2015, Brijwani N et al., Scientific Reports, 2017). After 6 cycles of therapy, following surgery, patients were clinically evaluated for response based on multiple criteria including radiological examination. This short-term clinical response was compared with CANScript driven response prediction. Results: Out of 25 evaluable patients, outcome is available for ten patients (40%) till today. Data indicate that CANScript derived predictive scores for responders and non-responders were highly correlated with clinical observation. For all six clinical non-responders, CANScript guided outcome was found to be matched with clinical outcome. Similarly, for rest 4 patients, while CANScript predicted response, 3 patients showed clinical response. These preliminary data from an ongoing study are encouraging and more patients will be enrolled and follow up data will be collected. Conclusion: Phenotypic assay based platform technologies are emerging as a new frontier of individual response prediction based on the complex and dynamic interplay of tumor and stroma including immune network. CANScript guided prediction of response showed encouraging results to understand the response of drugs at clinic, would offer further opportunity to incorporate phenotypic inputs for informed treatment decision in an adjuvant setting. [ABSTRACT FROM AUTHOR]