Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy

Murugan, Chandran; Rayappan, Kathirvel; Thangam, Ramar; Bhanumathi, Ramasamy; Shanthi, Krishnamurthy; Vivek, Raju; Ramasamy, Thirumurugan; Bhattacharyya, A.; Srinivasan, Sivasubramanian; Gunasekaran, Palani

doi:10.1038/srep34053

Cited by 99 publications

(87 citation statements)

References 76 publications

(88 reference statements)

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“…Rhodamine 123, a tracer dye which is able to enter the matrix and bind to mitochondria specifically, is widely used to detect the mitochondrial depolarization depending on the reduced fluorescence (15). The loss of ΔΨ m was assessed using FACSCalibur flow cytometry (16).…”

Section: Analysis Of Mitochondrial Membrane Potential (δψ M )mentioning

confidence: 99%

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

Luo

et al. 2018

Oncol Lett

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Abstract. Hypericum ascyron L. (Great St. Johnswort), which belongs to the Hypericaceae family, has been used for the treatment of hematemesis, metrorrhagia, rheumatism, swelling, stomach ache, abscesses, dysentery and irregular menstruation for >2,000 years in China. The aim of the present study was to clarify the anticancer activity compounds from H. ascyron L. and the underlying molecular mechanism. Anticancer activity of H. ascyron L. extract was evaluated using an MTT assay. To confirm the anticancer mechanism of activity compounds, Hoechst 33258, Annexin V-fluorescein isothiocyanate/propidium iodide, 2',7'-dichlorodihydrofluorescein diacetate, rhodamine 123 staining and caspase-3 activity analysis were performed. The results demonstrated that the anti-proliferative action of the mixture of kaempferol 3-O-β-(2"-acetyl) galactopyranoside (K) and quercetin (Q) (molar ratio, 1:1) was significantly increased compared with either of these two compounds separately, and the active fraction of the H. ascyron L. extract |(HALE). HALE, indicating that the anti-proliferative function of H. ascyron L. may be a synergic effect of K and Q. Furthermore, the inhibitory effect of KQ on the growth of HeLa cells was mediated by the induction of apoptosis. To the best of our knowledge, the present study is the first to identify that KQ exhibits significant anti-proliferation activity on HeLa cells via the apoptotic pathway, and is also the first to evaluate the anticancer potential of H. ascyron L. The results of the present study may provide a rational base for the use of H. ascyron L. in the clinic, and shed light on the development of novel anticancer drugs. IntroductionInvasive cervical cancer is one of the most common forms of female malignancies worldwide (1). According to an estimate, in 2008 alone there were ~530,000 novel cases of invasive cervical cancer and ~275,000 cervical cancer-associated mortalities worldwide (1,2). A growing number of young patients suffer from cervical cancer and the pathological types of the malignancies undergo changes (2). Current treatments for cervical cancer include surgery, radiation and chemotherapy, and conventional chemotherapy remains the most common treatment for advanced-stage cancers (3). In the last decade, increasing advances in cancer research have enhanced the understanding of cancer biology and genetics, and anticancer effects may be exhibited through selective cytotoxicity, anti-proliferative action, stimulation of apoptosis and induction of differentiation (4,5).Hypericum ascyron L. (Great St. Johnswort) has been used for the treatment of hematemesis, metrorrhagia, rheumatism, swelling, stomach ache, abscesses, dysentery and irregular menstruation for >2,000 years in China (6,7). H. ascyron L. extract has been investigated and revealed to exhibit anticancer activities (8,9). H. ascyron L. extract also possesses numerous other beneficial functions, including inhibition of histamine release (10), anti-inflammatory activity, analgesic effects (11), antioxidant activity (11),...

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Section: Analysis Of Mitochondrial Membrane Potential (δψ M )mentioning

confidence: 99%

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

Luo

et al. 2018

Oncol Lett

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“…cRGD peptide has shown a strong binding toward α v β 3 integrin-overexpressed MDA-MB-231 TNBC cells. [30][31][32] Interestingly, our results showed that cRGD-MMP can effectively target to and treat MDA-MB-231 cells in vivo. This micellar mertansine prodrug (MMP) has appeared as a promising platform for potent treatment of TNBC.…”

Section: Introductionmentioning

confidence: 69%

α<sub>v</sub>β<sub>3</sub> integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo

Zhong¹,

Gu²,

Cheng³

et al. 2017

IJN

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Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can effectively target and deliver DM1 to α v β 3 integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cRGD-MMP had obvious targetability to MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC 50 ) of 0.18 μM, which was close to that of free DM1 and 2.2-fold lower than that of micellar mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake and intracellular release of doxorubicin (used as a fluorescent anticancer drug model) in MDA-MB-231 cells. Notably, cRGD-MMP loaded with 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR could also accumulate in the tumor, although significantly less than cRGD-MMP. The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the tumor for cRGD-MMP at 12 h post injection. The therapeutic results demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at 1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by little body weight loss and histological analysis. This MMP has appeared as a promising platform for potent treatment of TNBCs.

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“…3d). Rhodamine 123, which is specifically located on mitochondria, is also widely used to detect mitochondrial membrane potential based on fluorescence intensity 27 . Our results show that cells treated with MPP + caused dose-dependent decreases in the fluorescence intensity of rhodamine 123 (Fig.…”

Section: Resultsmentioning

confidence: 99%

ROCK1/Drp1-mediated aberrant mitochondrial fission is crucial for dopaminergic nerve cell apoptosis

Zhang

Huang

et al. 2018

Preprint

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Dopamine deficiency caused by apoptosis of the dopaminergic nerve cells in the midbrain substantia nigra is the main pathological basis of Parkinson's disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays an important role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study shows that knockdown of Drp1 blocked aberrant mitochondrial fission and dopaminergic nerve cell apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell through suppression of Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms of a PD mouse model through inhibition of Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell. Collectively, Our study suggests an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via activation of Drp1-induced aberrant mitochondrial fission.

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Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy

Cited by 99 publications

References 76 publications

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

α<sub>v</sub>β<sub>3</sub> integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo

ROCK1/Drp1-mediated aberrant mitochondrial fission is crucial for dopaminergic nerve cell apoptosis

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Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy

Cited by 99 publications

References 76 publications

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

Induction of apoptosis in human cervical carcinoma HeLa cells by active compounds from Hypericumï¿½ascyron L.

&alpha;<sub>v</sub>&beta;<sub>3</sub> integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo

ROCK1/Drp1-mediated aberrant mitochondrial fission is crucial for dopaminergic nerve cell apoptosis

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α<sub>v</sub>β<sub>3</sub> integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo