Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin

Abstract

Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients.

Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway

“…Accumulating evidences show that silibinin, a classical anti-fibrosis drug, exhibits strong anti-cancer activity in several human malignant tumors ( Wu et al, 2013 ; Bosch-Barrera et al, 2016 ), but the underlying mechanism is still unknown. In consideration of one important molecule during fibrosis is LOX in hepatocyte, we suspected that whether the EGFR/LOX pathway plays a role in its anti-metastasis effect.…”

“…As reported, silibinin induces cancer cell cycle arrest ( Feng et al, 2015 ), apoptosis ( Zhang et al, 2015 ), inhibits tumor energy metabolism ( Raina et al, 2013 ), significantly inhibits tumor metastasis ( Bosch-Barrera and Menendez, 2015 ; Jiang C. et al, 2016 ). Importantly, Menendez’s study showed that lung cancer patients treated with silibinin had significantly inhibited brain metastasis in clinical ( Bosch-Barrera et al, 2016 ). Silibinin also showed a therapeutic effect on bladder cancers ( Wu et al, 2013 ), breast cancers ( Kim et al, 2016 ), prostate cancers ( Deep et al, 2014 ), liver cancers ( Polachi et al, 2016 ), etc.…”

“…It is a classical drug for hepatic fibrosis in clinical in many countries and regions. Interestingly, abundant studies and clinical trials 1 suggesting that silibinin exhibits anti-cancer effect, but the mechanism is incompletely understood ( Wu et al, 2013 ; Bosch-Barrera et al, 2016 ). As an anti-fibrotic drug, whether silibinin inhibiting metastasis via LOX requires further exploration.…”

Silibinin: an old drug for hematological disorders

“…We also find that, in hematological disorders, silibinin also can suppress the activation of some pathways, such as NPM-ALK, and then suppress its key downstream pSTAT3 [ 28 ]. It is noteworthy that, silibinin still have some limitation of clinical use: One of the biggest limitations in humans is its low oral bioavailability [ 41 ]. This forces us to seek new formulations.…”

Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways

“…Silibinin has been shown to have significant anti-cancer effects in a variety of cancer types [ 1 ], including prostate [ 1 – 3 ], bladder [ 4 , 5 ], kidney [ 6 , 7 ], skin [ 8 , 9 ], pancreas [ 10 ], breast [ 3 , 11 ], lung [ 12 – 14 ] and colon [ 15 , 16 ] cancers. Silibinin is also effective in inhibiting brain metastases from non-small cell lung cancer [ 17 ].…”