Correction: Jose et al. Transferrin-Conjugated Docetaxel-PLGA Nanoparticles for Tumor Targeting: Influence on MCF-7 Cell Cycle. Polymers 2019, 11, 1905.

In the original publication [...].

An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells.

Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 µM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin zymography. Inhibition of malignant cell migration was assessed by scratch wound assay. The compounds showed a decrease in cell migration and inhibition of induced MMP-2 and MMP-9 expression. NMJ-2 exhibited comparable activity to that of standard SAHA. Our findings indicate that NMJ series of compound have potent in vitro anti-cancer, anti-angiogenic and anti-metastatic activity through HDAC enzyme inhibition.

In vitro mechanistic and in vivo anti-tumor studies of Glycosmis pentaphylla (Retz.) DC against breast cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycosmis pentaphylla (Retz.) DC (Rutaceae) has been traditionally used for the treatment of rheumatism, cancer, liver disorders, inflammation etc. AIM OF THE STUDY: The present study is aimed at elucidating the effect of Glycosmis pentaphylla (Retz.) DC on the key markers of apoptosis, metastasis and angiogenesis, in vitro. The study also evaluated the effect of fractions in vivo in DMBA-induced mammary tumor model. MATERIALS AND METHODS: Fractions of Glycosmis pentaphylla (Retz.) DC leaf extracts was studied for their effect on apoptotic markers in breast cancer cell lines, MCF-7 and MDA-MB-231 cells. They were also studied for their effect on metastatic and angiogenic markers, MMP-9 and HIF-1α in MCF-7 cells. The fractions were studied in vivo in DMBA-induced mammary tumor model in Sprague Dawley rats. RESULTS: The studies showed that the fractions induced apoptosis in breast cancer cells through the intrinsic/mitochondrial apoptotic pathway. The fractions were also able to inhibit the metastatic and angiogenic markers, MMP-9 and HIF-1α. Anti-tumor studies in DMBA-induced mammary model in Sprague Dawley rats also showed favorable results.

In vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma.

The potential of cinnamic acid as an anti-inflammatory and anti-cancer agent has been studied previously. In our investigation, novel bio-isosters of cinnamyl sulfonamide hydroxamate were synthesized, characterized and confirmed for their structure and evaluated for cytotoxicity. Three NCEs namely, NMJ-1, -2 and -3 showed cell-growth inhibition in 6 human cancer cell lines with IC50 at the range of 3.3±0.15-44.9±2.6 µM. The hydroxamate derivatives of cinnamyl sulfonamide are reported inhibitors of HDAC enzyme. Thus, the effectiveness of these molecules was determined by whole cell HDAC assay in HCT 116 cell line. NMJ-2 (0.41±0.01 µM) exhibited better enzyme inhibition (IC50) compared to SAHA (2.63±0.07). In order to evaluate induction of apoptosis by treatment, Hoechst 33342 and AO/EB nuclear staining methods were used. Further, cell cycle analysis, Annexin V binding and caspase 3/7 activation assays were performed by flow cytometry where NMJ-2 significantly arrested the cell cycle at G2/M phase, increased Annexin V binding to the cell surface and activation of caspase-3/7. Bax/Bcl-2 ratio was observed by Western blot and showed an increase with NMJ-2 treatment. This was comparable to standard SAHA. The acute toxicity study (OECD-425) showed that NMJ-2 was safe up to 2000 mg/kg in rats. 1,2-Dimethyl hydrazine (DMH) was used to produce experimental colon adenocarcinoma in Wistar rats. 5-FU and NMJ-2 (100 mg/kg p.o. and 10 mg/kg i.p. once daily for 21 days, respectively) were administered to the respective groups. Both treatments significantly reduced ACFs, adenocarcinoma count, TNF-α, IL-6, nitrite and nitrate levels in colonic tissue. Our findings indicate that NMJ-2 has potent anti-cancer activity against colon cancer, by acting through HDAC enzyme inhibition and activation of intrinsic mitochondrial apoptotic pathway, with additional anti-inflammatory activity.

Glycosmis pentaphylla (Retz.) DC arrests cell cycle and induces apoptosis via caspase-3/7 activation in breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycosmis pentaphylla (Retz.) DC belonging to the family Rutaceae has been traditionally used for the treatment of rheumatism, anaemia, jaundice, skin diseases, bronchitis etc. The plant is traditionally considered as anti-cancer medicine and used by the healers of Bangladesh to treat all types of cancers. Perhaps the key to many of its medicinal applications is its inherent anti-inflammatory property. AIM OF THE STUDY: The present study is aimed at evaluating the effect of various fractions of G. pentaphylla (Retz.) DC leaves on the cell cycle and apoptosis of breast cancer cells viz. MCF-7 and MDA-MB-231. MATERIALS AND METHODS: Various extracts and fractions of the leaves of G. pentaphylla (Retz.) DC were studied for their cytotoxicity with the help of Sulforhodamine B assay, in MCF-7, MDA-MB-231 and Vero cell lines. The most active fractions were studied for their effect on the cell cycle of MCF-7 and MDA-MB-231 cells. Apoptotic studies were done using Hoechst staining, DNA fragmentation, Annexin V staining and caspase-3/7 activation assay in breast cancer cells. HPLC and HPTLC profiling of the active fractions were done. RESULTS: HPTLC and HPLC profiling revealed the presence of lupeol, chrysin, quercetin, ß-sitosterol and kaempferol as components in active fractions. Lupeol and chrysin are being reported in this plant for the first time. The studies showed that the selected fractions possess cell cycle inhibitory and apoptosis inducing effect on both MCF-7 and MDA-MB-231 cells. Apoptotic effect of the fractions on MCF-7 and MDA-MB-231 cells may be through the mitochondrial pathway by the activation of caspase-3/7.