Natural Products: Potential for Developing Phellodendron amurense Bark Extract for Prostate Cancer Management

Kumar, Addanki P.; Graham, Heather; Robson, Craig; Thompson, Ian M.; Ghosh, Rita

doi:10.2174/138955710791330936

Cited by 14 publications

(13 citation statements)

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“…Further, majority of approved anticancer drugs are either (i) natural products, (ii) derived semi-synthetically from natural products or (iii) synthetic products based on natural products (34–35). Although some of the currently used chemotherapeutic agents including paclitaxel are derived from natural products, natural products have not been comprehensively studied for their potential therapeutic benefits.…”

Section: Discussionmentioning

confidence: 99%

“…Although some of the currently used chemotherapeutic agents including paclitaxel are derived from natural products, natural products have not been comprehensively studied for their potential therapeutic benefits. Lack of thorough characterization, quality control including lack of understanding their mechanism of action limits their potential clinical utility (34–35). However, natural products or complex botanicals offer an added advantage by targeting multiple signaling pathways, deregulation of which is a characteristic feature of cancer (34, 35).…”

Section: Discussionmentioning

confidence: 99%

“…Lack of thorough characterization, quality control including lack of understanding their mechanism of action limits their potential clinical utility (34–35). However, natural products or complex botanicals offer an added advantage by targeting multiple signaling pathways, deregulation of which is a characteristic feature of cancer (34, 35). In this paper, we investigated the potential of Nx, a bark extract of Phellodendron amurense that is used as an anti-inflammatory agent in traditional Chinese medicine, to inhibit pancreatic cancer growth using in vitro and in vivo model systems and mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

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Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Gong

Xie

Bedolla

et al. 2014

Clinical Cancer Research

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Purpose Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of pancreatic cancer patients. Inflammatory molecules NFκB and Stat3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of the present study is to determine whether targeting Stat3/NFκB cross talk with a natural product Nexrutine (Nx) can inhibit inflammatory signaling in pancreatic cancer. Experimental design HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2 and AsPC-1 cells were tested for growth, apoptosis, Cox-2, NFκB and Stat3 level in response to Nx treatment. Transient expression, gel shift, ChIP was used to examine transcriptional regulation of Cox-2. Stat3 knockdown was used to decipher Stat3/NFκB cross talk. Histopathological and immunoblotting evaluation was performed on BK5-Cox2 transgenic mice treated with Nx. In vivo expression of prostaglandin receptor EP4 was analyzed in a retrospective cohort of pancreatic tumors using a TMA. Results Nx treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of Stat3, NFκB and their cross talk led to transcriptional suppression of Cox-2 and subsequent decreased levels of PGE2 and PGF2. Stat3 knockdown studies suggest Stat3 as negative regulator of NFκB activation. Nx intervention reduced the levels of NFκB, Stat3 and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors. Conclusions Dual inhibition of Stat3-NFκB by Nx may overcome problems associated with inhibition of either pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Gong

Xie

Bedolla

et al. 2014

Clinical Cancer Research

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“…Majority of approved anticancer drugs are either (i) natural products; (ii) derived semi‐synthetically from natural products; or (iii) synthetic products based on natural products . DX, one of synthetic product based on natural products, is widely used as chemotherapeutic agent to treat patients with advanced metastatic prostate cancer after the failure of androgen deprivation therapy .…”

Section: Discussionmentioning

confidence: 99%

Combination of Nexrutine and docetaxel suppresses NFκB‐mediated activation of c‐FLIP

Zhang

Wang

et al. 2017

Molecular Carcinogenesis

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Lack of effective options following failure to conventional chemotherapeutic agent such as Docetaxel (DX) is a major clinical challenge in the management of prostate cancer. These observations underscore the need for deciphering the underlying mechanism of DX resistance to enable the development of effective therapeutic approaches. We observed up regulation of the anti-apoptotic protein c-FLIP and its up stream regulators including receptor tyrosine kinase RON and transcription factor NFκB (p65) in tumors obtained from metastatic prostate cancer patients. We also observed significant downregulation of these molecules in prostate tumors isolated from patients treated with DX as first line therapy. Further, we identified the over the counter anti-inflammatory agent, Nexrutine (NX) suppresses c-FLIP protein levels, and expression in androgen-independent prostate cancer cells (PC-3). Remarkably, the observed decreased levels of c-FLIP were further reduced in combination with DX. Transient expression assays coupled with electrophoretic mobility shift and DNA affinity protein assay revealed that NX and DX suppresses c-FLIP promoter activity by preventing p65 binding. Notably, NX in combination with DX abolished binding of p65 to the c-FLIP promoter sequence containing NFκB binding sites. Biologically, these alterations resulted in reduced growth of PC-3 cells. Taken together, these observations suggest the utility of RON, p65, and c-FLIP as potential markers to predict response to DX treatment. Furthermore, our results also identified NX as an agent to potentiate the therapeutic response of DX by suppressing activation of c-FLIP and its upstream regulators.

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“…Still, given the significant toxicities associated with current treatments, scientifically validated efficacious natural supplements can serve as novel and effective alternative strategies for PC management (Kumar et al, 2010). In PC cells, aside from TAX, herbal agents including resveratrol, capsaicin, PC-SPES, Phellodendron amurense barks, Piper species, ginger and rosemary extracts have been observed to influence multiple mechanisms associated with PC (Kubota et al, 2000; Bonham et al, 2002; Bigler et al, 2003; Mori et al, 2006; Gill et al, 2007; Yesil-Celiktas 2010; Lopes et al, 2012; Oboh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Sensitivity and mechanisms of taxol-resistant prostate adenocarcinoma cells to Vernonia amygdalina extract

Cameron

Howard

Izevbigie

et al. 2013

Experimental and Toxicologic Pathology

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Prostate cancer (PC) patients once Paclitaxel (TAX) treatment responsive later develop hormone refractory PC, thus becoming TAX-insensitive. This underscores the urgent need to develop novel anti-PC therapies. Vernonia amygdalina (VA) could be one such candidate agent. We have shown that androgen-independent PC-3 cells are sensitive to VA treatment in-vitro. VA extract (0.01, 0.1 and 1mg/ml) inhibited DNA synthesis by 12%, 45%, (P<0.05), and 73% (P<0.01) respectively. In contrast, TAX (0.01, 0.1, and 1μM) failed to significantly affect cell growth, suggesting TAX resistance. We tested molecular mechanisms which may lend to the observed PC-3 cell VA sensitivity/TAX resistance. Though both VA and TAX stimulated MAPK activity, VA’s induction was more intense, but transient, compared to TAX’s sustained action. NF-κB activation was inhibited on average by 50% by either 1mg/ml VA or 1 μM TAX. VA extract caused 35% and 45% increases in c-Myc activity at 10 and 60 min intervals respectively, with the highest stimulation attained 1 hr after treatment. In contrast, similar levels were attained by TAX rapidly (within 5 min) and were sustained compared to the slow/multiphasic action of VA. VA extract treatments had no effect on AKT gene expression, while TAX treatments yielded a four-fold (P<0.01) increase; and P-glycoprotein (P-gp) activity was inhibited by VA and stimulated by TAX, compared to control (basal ATPase activity). This study shows that TAX-resistant PC-3 cells are sensitive to VA, perhaps explained by differential regulatory patterns of MAPK, c-Myc, AKT, and Pgp activities/expressions.

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Natural Products: Potential for Developing Phellodendron amurense Bark Extract for Prostate Cancer Management

Cited by 14 publications

References 0 publications

Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Combination of Nexrutine and docetaxel suppresses NFκB‐mediated activation of c‐FLIP

Sensitivity and mechanisms of taxol-resistant prostate adenocarcinoma cells to Vernonia amygdalina extract

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