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Review
. 2021 Jun 11;14(6):559.
doi: 10.3390/ph14060559.

Lung Cancer Management with Silibinin: A Historical and Translational Perspective

Sara Verdura  1   2 , Elisabet Cuyàs  1   2 , Verónica Ruiz-Torres  3 , Vicente Micol  3 , Jorge Joven  4 , Joaquim Bosch-Barrera  2   5   6 , Javier A Menendez  1   2
Affiliations
Review

Lung Cancer Management with Silibinin: A Historical and Translational Perspective

Sara Verdura et al. Pharmaceuticals (Basel). .

Abstract

The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.

Keywords: EMT; STAT3; metastasis; non-small cell lung cancer; silibinin; silymarin.

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Conflict of interest statement

Joaquim Bosch-Barrera reports grants and personal fees from Roche-Genentech, grants from Pfizer and Pierre Fabre, and personal fees from MSD, BMS, AstraZeneca, Boehringer-Ingelheim, and Novartis, outside the submitted work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Key milestones in the timeline of silibinin research in lung cancer. Originally employed as a hepatoprotectant and a remedy for the bites of poisonous snakes hundreds of years ago, silibinin has recently demonstrated significant clinical activity in patients with non-small cell lung cancer and brain metastases when used in new orally bioavailable formulations. Created with BioRender.
Figure 2
Figure 2
EML4-ALK-dependent chemosensitizing effects of silibinin in non-small cell lung cancer cells. We utilized the Phenotypic Microarray system, marketed and sold by Biolog (www.biolog.com, access date: 30 May 2021) to measure the sensitivity of an A549 non-small cell lung cancer (NSCLC) cell line with an EML4-ALK fusion isogenic oncogene (https://www.nature.com/articles/d42473-019-00011-z, access date: 30 May 2021) to a variety of growth inhibitors (in total, 92) in microplates (PM-M11 to PM-M14). This approach enables the simultaneous testing of tens of phenotypes and the identification of shared versus selective sensitivities to a wide variety of mechanistically distinct drugs. We chose a silibinin concentration of 100 µmol/L, which was notably lower than the IC50 value against A549 cells and consistently reduced cell viability by less than 5% in multiple experiments using the colorimetric redox-sensitive dye employed in the Biolog technology. A set of “negative” control plates cultured in the presence of the silibinin vehicle DMSO were used to assess the inherent response of A549/ALK+ A549 cells to growth inhibitors. A set of “positive” plates cultured in the presence of 100 µmol/L silibinin served to assess the nature of the interaction between silibinin and the 92 drugs pre-loaded in the 96-well plates (4 graded concentrations/each). We assessed the nature of the cytotoxic responses based on synergistic, additive, or antagonistic categories using an arbitrarily defined ratio of observed effect/theoretical effect, the so-called fractional effect (FE) method (Figure S1). Briefly, the theoretical effect of the combination was calculated by adding the effects of each drug used alone at the concentration tested in the combination to that obtained when silibinin was tested alone (i.e., “negative” control plates + effect of silibinin as single agent). This theoretical effect was compared with the actual effect obtained during the combinatorial experiment (“positive” plates, i.e., drugs in combination with silibinin) carried out strictly in parallel. The different interactions were then defined as follows: “additivity” was an observed effect equal to the theoretical effect, and the ratio between them ranged between 0.8 and 1.2; “synergy” was an observed effect higher than the theoretical effect, and the ratio between them was less than 0.8; and “antagonism” was an observed effect lower than the theoretical effect, and the ratio between them was more than 1.2. The interaction between silibinin and a given drug was initially scored as “synergistic” when at least two FEs were <0.8. A truly synergistic interaction was scored when data sets were re-assessed using a stricter threshold criterion (i.e., at least two FEs were <0.6). The representative immunoblots presented in the upper part of the figure show Western blot analyses of cell lysates from A549 parental cells and ALK + A549 derivatives cultured in the absence or presence of graded concentrations of silibinin (24 h) immunoblotted with anti-phospho-STAT3Tyr705, anti-total STAT3, and anti-β-actin. Created with BioRender. (+/−, plus/minus).
Figure 3
Figure 3
Silibinin mechanism of action in lung cancer: A STAT3-centric view. Aberrant activation of JAK/STAT3 signaling, in particular STAT3, participates in the initiation, development, and therapeutic resistance of lung cancer via promotion of proliferation, survival, inflammation, angiogenesis, and metastasis. Silibinin is a unique blocker of the JAK/STAT3 signal transduction cascade that operates as a bimodal SH2- and DBD-targeting direct STAT3 inhibitor (STAT3i) while sparing JAK activity. STAT3 participates in multiple layers of the EMT regulatory network, and feedback activation of STAT3 is a common cause of resistance to many chemotherapies and targeted cancer therapies. At the lung cancer cell-intrinsic level, silibinin-containing combinatorial treatments can overcome drug resistance and reduce the brain metastasis-initiating capacity of lung cancer cells. Brain metastasis cells promote the co-option of a pro-metastatic program driven by STAT3 activation in a subpopulation of reactive astrocytes surrounding metastatic lesions. Blocking microenvironmental STAT3 signaling in reactive astrocytes with silibinin reduces the growth of brain metastases from primary NSCLC tumors, even at advanced stages of colonization. Created with BioRender.
Figure 4
Figure 4
STAT3 Tyr705-dependent chemosensitizing effects of silibinin. We utilized the Phenotypic Microarray system, marketed and sold by Biolog (www.biolog.com, access date: 30 May 2021), to measure the sensitivity of DLD1 (STAT3WT/WT) cancer cells and a homozygous STAT3Y705F/Y705F knock-in isogenic derivative (Horizon Discovery, Cat.# HD 115-016) to a wide variety of 92 growth inhibitors in microplates (PM-M11 to PM-M14) following an identical procedure to that described in Figure 2. The representative immunoblots presented in the upper part of the figure show western blot analyses of cell lysates from DLD1 STAT3WT/WT parental cells and DLD1 STAT3Y705F/Y705F derivatives cultured in the absence or presence of graded concentrations of silibinin (24 h) immunoblotted with anti-phospho-STAT3Tyr705, anti-total STAT3, and anti-β-actin. Created with BioRender. (+/−, plus/minus).
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