Combination treatment with flavonoid morin and telomerase inhibitor MST-312 reduces cancer stem cell traits by targeting STAT3 and telomerase

Chung, Seyung; Oliva, Bryant; Dwabe, Sami; Vadgama, Jaydutt V.

doi:10.3892/ijo.2016.3546

Cited by 48 publications

(33 citation statements)

References 36 publications

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“…However, there are recent evidences of synergic action of MST-312 and other telomerase inhibitors on combination with classical drugs, 21,33,34 bringing new perspectives of use for this compound.…”

Section: Discussionmentioning

confidence: 99%

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Morais

Arcanjo

Lopes

et al. 2019

Cell Biochemistry & Function

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Telomerase is a good target for new anticancer drug development because it is present in over 85% of human tumours. However, despite chronic therapy is a condition for anti-telomerase approach, the effects of long-term treatment with telomerase inhibitors remain not well understood. In this work, it was evaluated the effects of long-term treatment of human MDA-MB-231 breast cancer cells with the telomerase inhibitor MST-312. Cells were treated for 72 hours or 140 days, and it was accessed their viability, proliferation rate, morphology, telomeric DNA content, and resistance mechanism. The drug had a clear short-term effect, including chemosensitizing cells for docetaxel and irinotecan, but the chronic exposition led to selection of long telomeres clones, changing characteristics of original cell line. This effect was confirmed in a clonal culture with homogenous karyotype. MRP-1 expression and alternative lengthening of telomeres (ALT) were discarded as additional mechanisms of resistance. This data suggest that, considering the intra-tumour heterogeneity (ITH), what is already a big challenge for treatment of cancer, chronic exposition to telomerase inhibitors can promote tumour adaptations with potential clinical repercussion, drawing attention to ongoing clinical trials and pointing important considerations most times neglected on studies about use of these inhibitors on cancer therapy.Significance of the study: Antitumour action of telomerase inhibitors is well known, but it depends on a long-term exposition because cells will undergo telomere erosion only after many duplication cycles. Recently, the frustrating results of clinical trials with these inhibitors aroused the interest of the scientific community to understand the mechanisms of resistance to anti-telomerase therapy. In this study, we conducted an 18-week experiment to show that telomerase inhibition can lead to cell adaptations and selection of long-telomeres clones, leading to acquisition of resistance. However, we also showed that this inhibitor can sensitize cells to the chemotherapeutic drugs docetaxel and irinotecan.

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Section: Discussionmentioning

confidence: 99%

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Morais

Arcanjo

Lopes

et al. 2019

Cell Biochemistry & Function

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“…Previous literature has shown that morin displays protective effects against oxidative stress‐induced cell damage in cells such as cardiovascular cells (Kok et al, ), hepatocytes (Singh, Jakhar, & Kang, ), and microglial cells (Dilshara, Jayasooriya, Lee, Choi, & Kim, ). Several studies reported that morin not only exerts the antioxidant properties but also acts as a possible chemo‐preventive agent by hindering tumor progression in many cancer types such as hepatocellular carcinoma (HCC) (Sivaramakrishnan & Devaraj, ) and colorectal cancer (CRC) (Chung, Oliva, Dwabe, & Vadgama, ).…”

Section: Discussionmentioning

confidence: 99%

Antigenotoxic effects of morin against lead induced genomic damage in cultured human peripheral blood lymphocytes

et al. 2019

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Lead (Pb) is a well‐known carcinogenic heavy metal. Exposure to Pb induces DNA damage by enhancing the generation of reactive oxygen species (ROS). One of the possible ways to shield DNA from this damage is to supply antioxidants that can remove free radicals generated by genotoxicants. Hence, the current study was designed to evaluate the antigenotoxic potential of a flavonoid compound; morin against Pb‐induced genomic damage on cultured human peripheral blood lymphocytes (PBL). The effect of Pb or morin or their combination was evaluated on the DNA damage using comet and sister chromatid exchange (SCE) assays. The results indicated a significant (p < 0.05) increase in the SCE frequency and various comet parameters in a dose‐dependent manner upon treatment with lead as compared to control in cultured PBL. Supplementation of morin along with Pb effectively negated DNA damage as measured by SCE frequency and comet parameters. Practical applications Results of our current study suggest that the DNA damage induced by genotoxicants can be overcome by co‐treatment with natural antioxidants, found in dietary supplements such as vegetables and fruits.

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“…Morin (3,5,7,2′,4′-pentahydroxyflavone) is a flavonoid (flavonol), originally extracted from plants of Moraceae family [20, 21]. The anticancer effect of morin has been well known by inhibiting proliferation of cells of multiple tumours, such as leukaemia [20], squamous cell carcinoma [20], colorectal cancer [20, 32], and breast cancer [33].…”

Section: Discussionmentioning

confidence: 99%

Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin

Bieg

Sypniewski

Nowak

et al. 2018

Arch Gynecol Obstet

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PurposeThis study aimed at evaluating whether morin (a natural flavonoid and a known inhibitor of NF-κB) can sensitize ovarian cancer cells to cisplatin by decreasing the expression of galectin-3, which is an anti-apoptotic protein regulated by NF-κB transcription factor.MethodsTo assess the possibility of augmentation the activity of cisplatin by morin, we studied the separate and the combined effect of morin and cisplatin on viability, proliferation, and apoptosis of TOV-21G (cisplatin-sensitive) and SK-OV-3 (cisplatin-resistant) ovarian cancer cells. We also analysed the effect of morin and cisplatin on galectin-3 expression at the mRNA and protein levels.ResultsWe demonstrated that morin possess antitumor activity against TOV-21G and SK-OV-3 ovarian cancer cells by reducing cell viability and proliferation as well as increasing the induction of apoptosis. Co-treatment of the cells with selected concentrations of morin and cisplatin, accordingly to specific treatment approaches, reveals a synergism, which leads to sensitization of the cells to cisplatin. During this sensitization, morin significantly reduces the expression of galectin-3 at the mRNA and protein level, regardless of the presence of cisplatin.ConclusionsMorin sensitizes TOV-21G and SK-OV-3 ovarian cancer cells to cisplatin, what is associated with a decrease of the expression of galectin-3.

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Combination treatment with flavonoid morin and telomerase inhibitor MST-312 reduces cancer stem cell traits by targeting STAT3 and telomerase

Cited by 48 publications

References 36 publications

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Antigenotoxic effects of morin against lead induced genomic damage in cultured human peripheral blood lymphocytes

Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin

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