Combination of Rapamycin and Resveratrol for Treatment of Bladder Cancer

Alayev, Anya; Salamon, Rachel S.; Schwartz, Naomi; Berman, Adi Y.; Wiener, Sara L.; Holz, Marina K.

doi:10.1002/jcp.25443

Cited by 44 publications

(36 citation statements)

References 51 publications

(58 reference statements)

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“…It has been reported that activation of PI3K/Akt signaling contributes to Derlin-1-mediated malignant phenotype in muscle invasive bladder cancer cells (8). Inhibition of PI3K/Akt signaling accounts for the induction of death in bladder cancer cells by combination treatment with rapamycin and resveratrol (9). These studies suggest that the PI3K/Akt pathway is an important target for anticancer treatment.…”

Section: Introductionmentioning

confidence: 83%

Genipin inhibits the growth of human bladder cancer cells via inactivation of PI3K/Akt signaling

Li¹,

Zhang

Jia

et al. 2017

Oncol Lett

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Abstract. Genipin, a natural compound derived from the fruit of Gardenia jasminoides, possesses numerous biological properties. The aim of the present study was to investigate the anticancer effects of genipin in human bladder cancer. T24 and 5637 bladder cancer cells were treated with different concentrations of genipin (0-200 µM) and tested for cell viability, colony formation, cell cycle progression and apoptosis. A xenograft model of bladder cancer was established to determine the anticancer effect of genipin in vivo. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of genipin was examined. Genipin treatment significantly inhibited the viability and clonogenic growth of bladder cancer cells and inhibited the growth of T24 xenograft tumors, compared with vehicle controls (P<0.05). Genipin-treated cells exhibited a cell cycle arrest at the G0/G1-phase, which was accompanied by a deregulation of numerous cell cycle regulators. Genipin-treated cells demonstrated a significant increase in the percentage of apoptotic cells, loss of mitochondrial membrane potential, Bax translocation to the mitochondria and the release of cytochrome c to the cytosol. Additionally, genipin treatment significantly (P<0.05) reduced the phosphorylation levels of PI3K and Akt in bladder cancer cells. Importantly, genipin-mediated anticancer effects were reversed by the overexpression of constitutively active Akt. In conclusion, to the best of our knowledge, the present study demonstrates for the first time the growth inhibitory effects of genipin in bladder cancer cells, and indicates its potential as a natural anticancer agent for bladder cancer.

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Section: Introductionmentioning

confidence: 83%

Genipin inhibits the growth of human bladder cancer cells via inactivation of PI3K/Akt signaling

Li¹,

Zhang

Jia

et al. 2017

Oncol Lett

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“…However, combination regimens of mTOR inhibitors together with current best-in class chemotherapeutics show efficacy against a range of cancers. For example, combination treatment with rapamycin and resveratrol may be effective in inducing cell death in bladder cancer cells [180], with resveratrol blocking the Akt activation induced by rapamycin. Similarly, rapamycin has been shown to enhance mitomycin C-induced apoptosis in peritoneal carcinomatosis [181].…”

Section: Age-related Cancermentioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

Preprint

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Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current therapies that effectively tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

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“…Similarly, hyperactivation of mTOR is associated with different types of cancer, such as bladder and breast cancer (11,39). Notably, combination regimen, such as rapamycin and resveratrol, have been identified to be effective in treating breast and bladder cancer by inducing autophagy and preventing reactivation of AKT1 in vitro and in a mouse xenograft model (40,41). Keeping the hypothesis in mind that both atypical PKC and mTOR serve crucial carcinogenic roles in bladder cancer cells, the present study aimed to inhibit both atypical PKC and mTOR in bladder cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of atypical protein kinase‑C and mTOR impedes bladder cancer cell progression

et al. 2020

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Despite enormous scientific advancements in cancer treatment, there is a need for research to combat cancer, particularly bladder cancer. Drugs once proved to be effective in treating bladder cancer have shown reduced efficacy; hence, the cancer recurrence rate is increasing. To overcome this situation, several strategies have been considered, including the development of novel active drugs or modification of existing therapeutic regimens by combining two or more existing drugs. In recent years, atypical protein kinase Cs (PKCs), phospholipid-dependent serine/threonine kinases, have been considered as a central regulator of various cancer-associated signaling pathways, and they control cell cycle progression, tumorigenesis and metastasis. Additionally, the biologically crucial mTOR signaling pathway is altered in numerous types of cancer, including bladder cancer. Furthermore, despite independent activation, atypical PKC signaling can be triggered by mTOR. The present study examined whether the concurrent inhibition of atypical PKCs and mTOR using a combination of novel atypical PKC inhibitors (ICA-I, an inhibitor of PKC-ι; or ζ-Stat, an inhibitor of PKC-ζ) and rapamycin blocks bladder cancer progression. In the present study, healthy bladder MC-SV-HUCT2 and bladder cancer TCCSUP cells were tested and subjected to a WST1 assay, western blot analysis, immunoprecipitation, a scratch wound healing assay, flow cytometry and immunofluorescence analyses. The results revealed that the combination therapy induced a reduction in human bladder cancer cell viability compared with control and individual atypical PKC inhibitor and rapamycin treatment. Additionally, the concurrent inhibition of atypical PKCs and mTOR retards the migration of bladder cancer cells. These findings indicated that the administration of atypical PKC inhibitors together with rapamycin could be a useful therapeutic option in treating bladder cancer.

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Combination of Rapamycin and Resveratrol for Treatment of Bladder Cancer

Cited by 44 publications

References 51 publications

Genipin inhibits the growth of human bladder cancer cells via inactivation of PI3K/Akt signaling

Genipin inhibits the growth of human bladder cancer cells via inactivation of PI3K/Akt signaling

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Simultaneous inhibition of atypical protein kinase‑C and mTOR impedes bladder cancer cell progression

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