Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells

Colombo, Valentina; Lupi, Monica; Falcetta, Francesca; Forestieri, Daniele; D’Incalci, Maurizio; Ubezio, Paolo

doi:10.1007/s00280-010-1335-8

Cited by 47 publications

(25 citation statements)

References 37 publications

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“…The RAR specific agonists, CD437 and AM580, were previously described (Gianni et al, 1996b), and the TGF-receptor kinase inhibitor, SB-431542, was from Sigma. Combination effects of lapatinib and ATRA were measured with the isobologram method (Colombo et al, 2011). Flowcytometric (fluorescence-activated cell sorting) analysis of DNA content was performed as described (Lupi et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

et al. 2011

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All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoidbased protocols. Here, we demonstrate that 23-32% of the human ERBB2 þ breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARa. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARa agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib þ ATRA. Induction of the retinoiddependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFb pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARa.

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Section: Methodsmentioning

confidence: 99%

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

et al. 2011

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“…Combination effects of PI-103 and rapamycin were quantified as described (ref. 21; Supplementary Methods). Experiments were run at least in triplicate.…”

Section: Cell Cultures and Drug Treatmentsmentioning

confidence: 99%

Combination of PI3K/mTOR Inhibitors: Antitumor Activity and Molecular Correlates

et al. 2011

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The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is a major target for cancer therapy. As a strategy to induce the maximal inhibition of this pathway in cancer cells, we combined allosteric mTOR inhibitors (rapamycin and RAD001) with a dual PI3K/mTOR kinase inhibitor (PI-103). Both in vitro and in vivo, the combination exhibited more activity than single agents in human ovarian and prostate cancer cells that harbor alterations in the pathway. At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation. Furthermore, the combination strongly inhibited the expression of PI3K/Akt/ mTOR downstream proteins. In particular, it showed greater activity than the single agents in inhibiting the phosphorylation of 4EBP1, both in vitro and in vivo, resulting in selective inhibition of CAP-dependent translation. A proteomic approach was used to confirm the identification of c-Myc as the key regulator for the reduction in downstream proteins affected by the combined inhibition of mTOR. In conclusion, the combination of a catalytic and an allosteric inhibitor of mTOR shows greater activity, without a concomitant increase in toxicity, than either drug alone, and this may have therapeutic implications for inhibiting this pathway in the clinical setting. Cancer Res; 71(13); 4573-84. Ó2011 AACR.

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“…A renoprotective effect of quercetin against cisplatin occurred without reducing the anti-tumour activity of this drug (19). A lack of negative interference of silymarin with anti-tumour effects of drugs has been reported by other researchers as well (20). In fact, silymarin and its main flavonolignan, silybin, have shown both in vivo and in vitro anticancer effects against skin, breast, lungs, colon, bladder, prostate and kidney carcinomas (21).…”

Section: Silymarin and Cisplatin-induced Nephrotoxicitymentioning

confidence: 87%

Potential Renoprotective Effects of Silymarin Against Nephrotoxic Drugs: A Review of Literature

Shahbazi¹,

Dashti‐Khavidaki²,

Khalili³

et al. 2012

J Pharm Pharm Sci

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Drug-induced nephrotoxicity (DIN) accounts for up to sixty percent of hospital acquired acute kidney injury. Several efforts have been made to reduce drug-induced renal damage; however, DIN remains a matter of concern, with substantial impact on patients and the health system. Silymarin is a drug that has been used for many years in alternate and modern medicine for treating hepatic diseases. Its antioxidant, anti-inflammatory and anti-apoptotic effects make it an interesting herbal medicine, and these properties have implicated this compound as a potential renoprotective agent. Based on the findings from animal studies, this review concluded that silymarin might exert significant protective or ameliorative effects against drug-induced kidney disease, especially against cisplatin-induced renal damage. Whether the protective administration of silymarin could be an effective clinical pharmacological strategy to prevent DIN is a question that remains to be answered in clinical trials. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells

Cited by 47 publications

References 37 publications

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

Combination of PI3K/mTOR Inhibitors: Antitumor Activity and Molecular Correlates

Potential Renoprotective Effects of Silymarin Against Nephrotoxic Drugs: A Review of Literature

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