Corrigendum: Blockade of uttroside B-induced autophagic pro-survival signals augments its chemotherapeutic efficacy against hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.812598.].

Corrigendum: Cucurbitacin B, purified and characterized from the rhizome of Corallocarpus epigaeus exhibits anti-melanoma potential.

[This corrects the article DOI: 10.3389/fonc.2022.903832.].

Cucurbitacin B, Purified and Characterized From the Rhizome of Corallocarpus epigaeus Exhibits Anti-Melanoma Potential.

The ethnomedicinal plant from the Cucurbitaceae family, Corallocarpus epigaeus, or its bioactive derivatives have been widely utilized in traditional medicine owing to their distinct applications against various human ailments and have lured the interest of ethnobotanists and biochemists. Here, we report for the first time, the anti-cancer potential of a bio-active fraction isolated from the dried rhizome of C. epigaeus, and the bioactive principle identified as cucurbitacin B (Cu-B). The purification processes involving the utilization of multiple organic extracts of C. epigaeus rhizome powder, yielded Cu-B from the Ethyl acetate Cytotoxic Fraction (ECF), obtained by the chromatographic separation of the ethyl acetate extract. Amongst the various cancer lines tested, melanoma cells exhibit maximal sensitivity towards the Cu-B-containing ECF fraction. Cu-B induces an apoptotic mode of cell death initiated intrinsically as well as extrinsically in A375 melanoma cells whilst remaining comparatively less toxic to normal skin fibroblasts. In vivo studies involving a NOD-SCID murine model of human melanoma demonstrate the ability of Cu-B to attenuate tumor growth, while being pharmacologically safe in vivo, as assessed in Swiss albino mice. Furthermore, Cu-B inhibits MEK 1/2 as well as the constitutive and EGF-induced ERK 1/2 activation, indicating a definitive involvement of MAPK signal transducers in regulating Cu-B-mediated anti-melanoma activity. Together, our study demonstrates the anti-melanoma potential of C. epigaeus-derived Cu-B, which indicates the Cucurbitaceae succulent as a prospective source for deriving potent and pharmacologically safe anti-cancer compounds.

Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells.

Diindolylmethane (DIM) is a metabolic product of indole-3-carbinol (I3C), the major phytochemicals present in cruciferous vegetables, which can modulate multiple signalling pathways in cancer. The present study deals with the mechanism of action of two synthetic biaryl conjugates of DIM in triple negative breast cancer cells. Out of 12 DIM derivatives tested, two compounds, DIM-1 and DIM-4, exhibit cytotoxicity with GI50 values of 9.83 ± 0.2195 µM and 8.726 ± 0.5234 µM, respectively, in 2D culture. In 3D culture, DIM-1 and DIM-4 show GI50 values of 24.000 ± 0.7240 µM and 19.230 ± 0.3754 µM, respectively. The non-toxic nature of the compounds was also established by the toxicity studies using the zebrafish model system. The two compounds induced apoptosis and anoikis in the cancer cells, which was confirmed by morphological analysis, nuclear fragmentation, membrane integrity assay, caspase activity measurements and modulation of pro/anti-apoptotic proteins. The compounds inhibited cell migration and MMP-2 and MMP-9 activities indicating their anti-metastatic property. They also reduced the expression of active Ras, phosphorylated forms of PI3K, Akt and mTOR. Immunofluorescence studies revealed the reduced expression of EGFR and pEGFR in treated cells. To conclude, DIM-1 and DIM-4 induced anti-breast cancer effects by blocking EGF receptor and subsequently inhibiting Ras-mediated PI3K-Akt-mTOR signalling pathway.

Blockade of Uttroside B-Induced Autophagic Pro-Survival Signals Augments Its Chemotherapeutic Efficacy Against Hepatocellular Carcinoma.

Our previous study has demonstrated that Uttroside B (Utt-B), a saponin isolated from the leaves of Solanum nigrum Linn induces apoptosis in hepatic cancer cells and exhibits a remarkable growth inhibition of Hepatocellular Carcinoma (HCC). Our innovation has been granted a patent from the US (US 2019/0160088A1), Canada (3,026,426.), Japan (JP2019520425) and South Korea (KR1020190008323) and the technology have been transferred commercially to Q Biomed, a leading US-based Biotech company. Recently, the compound received approval as 'Orphan Drug' against HCC from US FDA, which reveals the clinical relevance of evaluating its antitumor efficacy against HCC. In the present study, we report that Utt-B promotes pro-survival autophagy in hepatic cancer cells as evidenced by the increased expression of autophagy-related proteins, including LC3-II, Beclin1, ATG 5, and ATG 7, as well as a rise in the autophagic flux. Hence, we investigated whether Utt-B-induced autophagic response is complementing or contradicting its apoptotic program in HCC. Inhibition of autophagy using the pharmacological inhibitors, Bafilomycin A1(Baf A1), and 3-methyl adenine (3-MA), and the biological inhibitor, Beclin1 siRNA, significantly enhances the apoptosis of hepatic cancer cells and hence the cytotoxicity induced by Utt-B. We also found increased expression of autophagy markers in Utt-B-treated xenografts derived from HCC. We further analyzed whether the antimalarial drug, Chloroquine (Cqn), a well-known autophagy inhibitor, can enhance the anticancer effect of Utt-B against HCC. We found that inhibition of autophagy using Cqn significantly enhances the antitumor efficacy of Utt-B in vitro and in vivo, in NOD SCID mice bearing HCC xenografts. Taken together, our results suggest that the antitumor effect of Utt-B against HCC can be further enhanced by blocking autophagy. Furthermore, Utt-B in combination with Cqn, a clinically approved drug, if repurposed and used in a combinatorial regimen with Utt-B, can further improve the therapeutic efficacy of Utt-B against HCC.

Semi-synthetic diversification of coronarin D, a labdane diterpene, under Ugi reaction conditions.

The prevalence of 5-hydroxydihydrofuran-2(3H)-one moiety in natural products is exploited for the first time using coronarin D, a labdane diterpene, to afford Ugi reaction product 1a and interrupted Ugi product 2a. The potential of the Ugi reaction was further extended to l-phenylalanine, 2-aminopyridine, and d-glucosamine, which afforded Ugi reaction products 3a-f, 4, and 5a-d, respectively. Cytotoxicity studies in RAW cells reveal that compounds 3e and 5b were non-toxic up to 50 µM, and these compounds were able to reduce the LPS stimulated NO production in RAW cells in par with the standard anti-inflammatory drug dexamethasone.

Spice-infused palmyra palm syrup improved cell-mediated immunity in Wistar Albino rats.

Spices attract tremendous attention in the management of viral infections. However, scientific validation is vital to recommend spices as nutraceuticals or functional foods. In the present work, we have selected three spices based on Ayurvedic knowledge and developed a nutraceutical for immunomodulation. Trikatu, a blend of ginger, black pepper, and long pepper, is used in the Indian Ayurvedic system, along with many herbs, for various ailments. We formulated a "Trikatu syrup" (TS) using these three spices and palmyra palm neera. Carbon clearance assay, neutrophil adhesion test, and sheep red blood cell (SRBC)-induced delayed-type hypersensitivity (DTH) reaction was performed to investigate the immunomodulatory potential of TS in Wistar Albino rats. The rats fed with TS showed a dose-dependent increase in footpad thickness compared to control rats, suggesting cell-mediated immunity. The major bioactive piperine in TS was isolated and quantified. PRACTICAL APPLICATIONS: Spices are consumed worldwide as a flavor enhancer in food. Besides, spices have an array of bioactive molecules with a multitude of health benefits. In the backdrop of COVID-19, immunomodulation and antiviral properties of spices are discussed widely. The present study is intended to explore the potential of three selected spices (ginger, black pepper, and long pepper) beyond its application in typical food preparations. The syrup formulated in this study by using these three spices improved cell-mediated immunity in Wistar Albino rats. The study warrants further validation studies of the formulated product for providing indisputable claims for the immunomodulation properties.

Anticancer activity of synthetic bis(indolyl)methane-ortho-biaryls against human cervical cancer (HeLa) cells.

Bis(indolyl)methane appended biaryls were designed, synthesized and evaluated in human cervical cancer cell lines (HeLa) for their anticancer activities and compared against normal rat cardiac myoblasts (H9C2) cells. Compounds 1-12 were synthesized, with variations in one of the phenyl unit, in a single step by condensation of biaryl-2-carbaldehydes with indole in the presence of para-toluenesulfonic acid. Compound 1 exhibited a GI50 value of 11.00 ± 0.707 µM and the derivatives, compounds 4 and 11 showed a GI50 value of 8.33 ± 0.416 µM and 9.13 ± 0.177 µM respectively in HeLa cells and was found to be non-toxic to H9C2 cells up to 20 µM. Furthermore, compounds 1, 4 and 11 induced caspase dependent cellular apoptosis in a concentration-dependent manner, reduced mitochondrial membrane potential, inhibited the cell migration and downregulated the production of MMP-2 and MMP-9 in HeLa cells.