PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]

Booth, Laurence; Roberts, Jeanette C.; Poklepovic, Andrew; Dent, Paul

doi:10.18632/oncotarget.14562

Cited by 12 publications

(11 citation statements)

References 39 publications

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“…Over the next 6-18 months the NSCLC tumors evolve so that they become resistant to the kinase inhibitory drugs. It is known from in vitro studies that ERBB1 inhibitors reduce the expression of immunotherapy biomarkers such as PD-L1 in NSCLC cells and tumors from kinase inhibitor resistant patients express low levels of PD-L1 and PD-L2 [ 43 , 44 , 45 – 46 ]. In NSCLC, low levels of immunotherapy biomarkers correlate with a poor anti-tumor response to anti-PD-1 and anti-CTLA4 inhibitory antibodies.…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

et al. 2017

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Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles. Combined exposure of cells to [neratinib + HDAC inhibitors] caused inactivation of mTORC1 and mTORC2, enhanced autophagosome and subsequently autolysosome formation, and caused an additive to greater than additive induction of cell death. Knock down of Beclin1 or ATG5 prevented HDAC inhibitors or neratinib from reducing ERBB1/3/4 and K-/N-RAS expression and reduced [neratinib + HDAC inhibitor] lethality. Neratinib and HDAC inhibitors reduced the expression of multiple HDAC proteins via autophagy that was causal in the reduced expression of PD-L1, PD-L2 and ornithine decarboxylase, and increased expression of Class I MHCA. In vivo, neratinib and HDAC inhibitors interacted to suppress the growth of 4T1 mammary tumors, an effect that was enhanced by an anti-PD-1 antibody. Our data support the premises that neratinib lethality can be enhanced by HDAC inhibitors, that neratinib may be a useful therapeutic tool in afatinib resistant NSCLC, and that [neratinib + HDAC inhibitor] exposure facilitates anti-tumor immune responses.

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Section: Discussionmentioning

confidence: 99%

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

et al. 2017

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“…(50) The antitumor effect of sorafenib and pemetrexed combination was additionally enhanced by PDE5 inhibitors in NSCLC cells. (51) Varinostat, when combined with gefitinib, strongly inhibited the growth of mutant KRAS lung cancer cells and hepatocarcinoma, but the combination of sorafenib and varinostat did not show such an effect. (52) In conclusion, the present study showed that sorafenib in combination with betulinic acid enhanced the inhibitory effect on NSCLC cells.…”

Section: Discussionmentioning

confidence: 98%

“…Sorafenib combined with gemcitabine or pemetrexed generated a synergistic effect against the A549 cell line . The antitumor effect of sorafenib and pemetrexed combination was additionally enhanced by PDE5 inhibitors in NSCLC cells . Varinostat, when combined with gefitinib, strongly inhibited the growth of mutant KRAS lung cancer cells and hepatocarcinoma, but the combination of sorafenib and varinostat did not show such an effect …”

Section: Discussionmentioning

confidence: 99%

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

2017

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The highly selective multi‐targeted agent sorafenib is an inhibitor of a number of intracellular signaling kinases with anti‐proliferative, anti‐angiogenic and pro‐apoptotic effects in various types of tumors, including human non‐small cell lung cancer (NSCLC). Betulin displays a broad spectrum of biological and pharmacological properties, including anticancer and chemopreventive activity. Combination of drugs with different targets is a logical approach to overcome multilevel cross‐stimulation among key signaling pathways in NSCLC progression. NSCLC cell lines, A549, H358 and A427, with different KRAS mutations, and normal human peripheral blood lymphocyte cells, were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of different combined treatments on viability (MTS test), proliferation and apoptotic susceptibility based on flow cytometry, alterations in signaling pathways by western blotting and colony‐forming ability. The combination of sorafenib with betulinic acid had a strong effect on the induction of apoptosis of different NSCLC cell lines. In addition, this combination was not toxic for human peripheral blood lymphocytes. Combination treatment changed the expression of proteins involved in the mitochondrial apoptosis pathway and induced apoptotic death by caspase activation. Importantly, combination treatment with low drug concentrations tremendously reduced the colony‐forming ability of A549, H358 and A427 cells, as compared to both compounds alone. In this study, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to induce high levels of cell death and abolish clonogenic activity in some NSCLC cell lines regardless of KRAS mutations.

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“…[ 41 ] showed the synthetic lethality of the combination of sildenafil, vardenafil or tadalafil with pemetrexed in non-small cell lung cancer (NSCLC) cell lines and in vivo of the combination of sildenafil (5 mg/kg) and pemetrexed. The work has also been extended to show that the combination of sildenafil, pemetrexed and sorafenib enhances the in vivo anti-tumour effects of the pemetrexed + sorafenib combination in a H460 NSCLC model [ 42 ], the combination of celecoxib, sildenafil and sorafenib in a panel of ovarian cancer cells lines [ 43 ] and pemetrexed, sildenafil and sodium valproate in NSCLC and ovarian cell lines [ 44 ]. Domvri et al .…”

Section: Pre-clinical Evidence In Cancer— In Vitro mentioning

confidence: 99%

Repurposing drugs in oncology (ReDO)—selective PDE5 inhibitors as

Pantziarka

Sukhatme²,

Crispino

et al. 2018

ecancer

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Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

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PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib]

Cited by 12 publications

References 39 publications

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

Repurposing drugs in oncology (ReDO)—selective PDE5 inhibitors as

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