Steroidal Saponins: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Amr Amin.

Cancer is a global health burden responsible for an exponentially growing number of incidences and mortalities, regardless of the significant advances in its treatment. The identification of the hallmarks of cancer is a major milestone in understanding the mechanisms that drive cancer initiation, development, and progression. The hallmarks of cancer have been targeted to effectively treat various types of cancers. These conventional cancer drugs have shown significant therapeutic efficacy but continue to impose unfavorable side effects on patients. Naturally derived compounds are being tested in the search for alternative anti-cancer drugs. Steroidal saponins are a group of naturally occurring compounds that primarily exist as secondary metabolites in plant species. Recent studies have suggested that steroidal saponins possess significant anti-cancer capabilities. 

  • steroidal saponins
  • cancer
  • natural products
  • hallmarks of cancer
  • cancer treatment
  • mechanism of cancer

1. Inhibition of Replicative Immortality

Telomeres are repetitive regions of DNA existing at the ends of chromosomes. Normally, telomeres decrease in length with every successive round of replication. This phenomenon contributes to a cell’'s mortality as the erosion of telomeric DNA leads to cellular senescence and ultimately cell death. Cancer cells circumvent this limited replicative potential and become immortal with an unlimited life span. They attain this capability primarily by overexpressing telomerase to ensure extended telomeres [2][1].
Diosgenin was shown to inhibit the expression of the telomerase reverse transcriptase (TERT) gene of rat C6 and human T98G glioblastoma cell lines. This gene encodes for an essential subunit of telomerase, and its inhibition prevents the maintenance of extended telomeres in cancer cells [34][2]. Diosgenin also inhibited the human telomerase reverse transcriptase (hTERT) gene expression in A549 cells verified by qRT-PCR analysis. Pure diosgenin had a greater impact on hTERT inhibition as opposed to fenugreek extract diosgenin [36][3].

2. Inhibition of Tumor Promoting Inflammation

Inflammatory conditions have been long known to be a breeding ground for the development and progression of various tumors. In the setting of chronic inflammation, growth factors and cytokines are released from immune cells into the tumor microenvironment, thereby promoting the growth of tumors [2][1]. Targeting this tumor-promoting inflammation is a major therapeutic intervention for the treatment of cancer. Studies have indicated that steroidal saponins have the ability to suppress tumor-promoting inflammation by inhibiting inflammatory signaling pathways.
The steroidal saponin Diosgenin decreased inflammation in the NSCLC cell line A549 by modulating NF-kB signaling [35][4]. The transcription factor NF-kB is essential for the transcription of pro-inflammatory genes such as those encoding for COX-2 and is overexpressed in numerous cancers [79][5]. The detection of NF-kB via fluorescence immunocytochemistry indicated that diosgenin inhibits the nuclear import of NF-kB and consequently prevents the expression of pro-inflammatory genes. This was verified by a reduction in COX-2 and PGE2 expression as a result of diosgenin treatment according to Western blot analysis [35][4].
Tumor-associated macrophages (TAM) facilitate the growth and proliferation of tumors and have a critical role in the tumor microenvironment. Dioscin caused a phenotypic shift of pro-tumorigenic M2-like TAMs into the tumor-suppressing M1-like TAMs in the Raw264.7 cell line. It also limited the secretion of cytokines such as IL-10 and induced the phagocytosis BMDMs. These results were further verified in a subcutaneous lung tumor animal model [80][6].
RCE-4 obtained from Reineckia carnea exerted anti-inflammatory activities in a human cervical cancer Caski cell xenograft mouse model. Paclitaxel was used as a reference drug in this investigation. RCE-4 caused a reduction in the COX-2 expression, which was assessed via immunohistochemical analysis. This effect was comparable to that of paclitaxel but did not outperform palitaxel’s overall tumor-suppressing activities in the animal model [68][7].

3. Inhibition of Tumor Invasion and Metastasis

A common feature shared among malignancies is their ability to spread throughout an organism and colonize different sites. Cancer cells are subjected to various molecular and genetic modifications that allow them to migrate and conform to new distant microenvironments [2][1]. Considering that the metastatic potential of tumors is a major contributor to the lethality of cancer, it is important that this feature is targeted when developing cancer treatments [81][8]. Steroidal saponins have been shown to alleviate this hallmark of cancer by inhibiting key players in tumor metastasis and invasion. This includes Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs).
The steroidal saponin protodioscin mitigates 5637 and T24 bladder cancer cell migration and invasion. This was assessed using a wound-healing assay, motility assay, and a transwell Matrigel invasion assay. Since EMT is linked to the metastatic abilities of cancer cells, associated proteins were evaluated in a Western blot. The results indicated a downregulation in N-cadherin and an upregulation in E-cadherin protein expression, confirming the inhibition of tumor metastasis [43][9].
The steroidal saponin A-24 inhibited the migration of gastric cancer cell lines. p53-deficient KATO-III cells and p53 wild-type gastric cancer cells were utilized in this restudyearch to determine the role of p53 in cancer cell migration and invasion. The downregulation of MMP-2 expression and a reduction in transwell migration and wound closure rates were observed in a dose-dependent manner. These results were independent of p53 status [21][10].
Bufalin prevented cancer cell invasion and migration in the gallbladder cancer cell line GBC-SD according to transwell migration and invasion results. It also lowered the expression of Snail and MMP9 while increasing the E-cadherin levels. Since cancer stem cells promote metastasis, stemness marker proteins CD133, CD44, Sox2, Oct4, and Nanog were assessed. The expression of these proteins was almost diminished after bufalin treatment [25][11].
Trillin derived from Trillium tschonoskii prohibited the migration and invasion of the liver cancer cell lines HepG2 and PLC/PRF5, as indicated in a wound healing assay. Genes involved in cell migration and invasion were suppressed after trillin treatment, as confirmed by Western blot and qPCR results. A significant reduction in the expression of STAT3, MMP1, MMP2, MucI, and VEGF was observed. This restudyearch suggested that trillin mainly targets STAT3, which is responsible for the expression of genes encoding for proteins with significant roles in the migration and invasion of tumor cells [47][12].
The total steroidal saponins from Paris polyphylla (PPSS) were shown to limit the migration and invasion of A549 cells. This was evaluated by Matrigel invasion chamber and wound-healing assays. PPSS suppressed the expression and activity of the metalloproteinases MMP-2 and MMP-9, as indicated by Western blot and gelatin zymography results [82][13]. Major constituents of PPSS included polyphyllin I, polyphyllin II, and polyphyllin E.
Polyphyllin I restricted the proliferation and invasion of the cisplatin-resistant gastric cancer cell line SGC7901/DDP via the modulation of the CIP2A/PP2A/Akt pathway. CIP2A plays an essential role in tumor metastasis and EMT and its upregulation is often observed in gastric cancer. Polyphyllin I also decreased tumor volume and CIP2A, phospho-Akt, and vimentin expression in a xenograft murine model [58][14]. These results were consistent with the treatment of prostate cancer with polyphyllin I in vitro and in vivo [60][15]. It was also reported that polyphyllin I inhibited the migration of the osteosarcoma cancer cell lines 143-B and HOS in a wound-healing assay and a xCELLigence RTCA DP system. This inactivation of EMT is ascribed to the polyphyllin I-mediated inhibition of Wnt/β-catenin signaling [59][16].
Polyphyllin II suppressed tumor cell motility, as observed in wound-healing assays. It also reduced cofilin activity and MMP2, and MMP9 expression in the liver cancer cell lines HepG2 and BEL7402. This inhibition of tumor cell motility was achieved as polyphyllin II targets Akt/NF-kB signaling [49][17]. These effects were comparable to the treatment of ovarian cancer cell lines SK-OV-3 and OVCAR-3 with polyphyllin E. MMP2 and MMP9 were downregulated primarily via the inhibition of the Akt/NF-kB pathway post-polyphyllin E treatment [51][18]. In another study, polyphyllin II inhibited the migration of T24 and 5637 bladder cancer cells in a wound-healing assay. It significantly decreased N-cadherin, MMP2, MMP9, and other EMT-associated proteins to a level resembling that of normal cells [50][19].

4. Inhibition of Abnormal Metabolism

Considering the rapid growth and proliferation of cancer cells, an increased demand for energy is required to sustain such processes. Therefore, cancer cells must rewire their metabolic programs to meet these high demands. However, this metabolic reprogramming of cancer cells poses a paradox since relatively inefficient glycolysis is the preferred mode of energy production for cancer cells, even under aerobic conditions. The term “aerobic glycolysis” is used to describe the glucose metabolism of cancer cells even in the presence of oxygen. This phenomenon is known as the Warburg effect [2][1]. It is important to note that in instances of glucose deprivation, cancer cells resort to mitochondrial metabolic pathways rather than aerobic glycolysis to meet their energy demands. The modulation of both of these metabolic pathways may be a more effective approach to terminating cancer cells [83][20].
The steroidal saponin gracillin was found to inhibit both aerobic glycolysis and OXPHOS in H460 and H226B NSCLC cells, thereby depriving tumor cells of all modes of ATP synthesis [38][21]. The anti-glycolytic effects of the steroidal saponin were confirmed by the modulation of metabolites involved in glycolysis, a decrease in lactate production, and the extracellular acidification rate following the gracillin treatment. The same results were observed in triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. The downregulation of the mitochondrial function and consequently OXPHOS was evaluated using the MTT assay. The best results were observed when gracillin was combined with the OXPHOS-mediated energy production inhibitors antimycin or oligomycin [38][21].
Dioscin demonstrated inhibitory effects on glycolysis in the colorectal cancer cell lines DLD1, HCT116, SW480, HT29, HCT8, and SW620 [29][22]. The protein Skp2 is overexpressed in colorectal cancers and is important for glycolysis to take place. It also promotes the expression of Glut1 transporters, which are essential for the increased influx of glucose into cancer cells to compensate for the low yield of ATP from aerobic glycolysis [84][23]. Dioscin markedly reduced glycolysis by attenuating phosphorylated Skp2 levels in the colorectal cancer cell lines. The effects of dioscin were further investigated in a xenograft model in which the expression of Skp2 was also reduced [29][22]. A notable characteristic of the Warburg effect is the cellular utilization of glutamine as an energy source and as a precursor for the synthesis of cellular components [85][24]. Dioscin was reported to interfere with D-glutamine metabolism in a SW480 rectal cancer cell line. Aerobic glycolysis is characterized by an increase in lactic acid production as pyruvic acids are converted into lactic acids. Dioscin also downregulated L-lactic acid levels in the same cancer cell line, suggesting the inhibition of aberrant pyruvate metabolism [86][25].

4. Inhibition of Replicative Immortality

Telomeres are repetitive regions of DNA existing at the ends of chromosomes. Normally, telomeres decrease in length with every successive round of replication. This phenomenon contributes to a cell’s mortality as the erosion of telomeric DNA leads to cellular senescence and ultimately cell death. Cancer cells circumvent this limited replicative potential and become immortal with an unlimited life span. They attain this capability primarily by overexpressing telomerase to ensure extended telomeres [2][1]. Diosgenin was shown to inhibit the expression of the telomerase reverse transcriptase (TERT) gene of rat C6 and human T98G glioblastoma cell lines. This gene encodes for an essential subunit of telomerase, and its inhibition prevents the maintenance of extended telomeres in cancer cells [34][2]. Diosgenin also inhibited the human telomerase reverse transcriptase (hTERT) gene expression in A549 cells verified by qRT-PCR analysis. Pure diosgenin had a greater impact on hTERT inhibition as opposed to fenugreek extract diosgenin [36][3].

5. Inhibition of Tumor Promoting Inflammation

Inflammatory conditions have been long known to be a breeding ground for the development and progression of various tumors. In the setting of chronic inflammation, growth factors and cytokines are released from immune cells into the tumor microenvironment, thereby promoting the growth of tumors [2][1]. Targeting this tumor-promoting inflammation is a major therapeutic intervention for the treatment of cancer. Studies have indicated that steroidal saponins have the ability to suppress tumor-promoting inflammation by inhibiting inflammatory signaling pathways. The steroidal saponin Diosgenin decreased inflammation in the NSCLC cell line A549 by modulating NF-kB signaling [35][4]. The transcription factor NF-kB is essential for the transcription of pro-inflammatory genes such as those encoding for COX-2 and is overexpressed in numerous cancers [79][5]. The detection of NF-kB via fluorescence immunocytochemistry indicated that diosgenin inhibits the nuclear import of NF-kB and consequently prevents the expression of pro-inflammatory genes. This was verified by a reduction in COX-2 and PGE2 expression as a result of diosgenin treatment according to Western blot analysis [35][4]. Tumor-associated macrophages (TAM) facilitate the growth and proliferation of tumors and have a critical role in the tumor microenvironment. Dioscin caused a phenotypic shift of pro-tumorigenic M2-like TAMs into the tumor-suppressing M1-like TAMs in the Raw264.7 cell line. It also limited the secretion of cytokines such as IL-10 and induced the phagocytosis BMDMs. These results were further verified in a subcutaneous lung tumor animal model [80][6]. RCE-4 obtained from Reineckia carnea exerted anti-inflammatory activities in a human cervical cancer Caski cell xenograft mouse model. Paclitaxel was used as a reference drug in this investigation. RCE-4 caused a reduction in the COX-2 expression, which was assessed via immunohistochemical analysis. This effect was comparable to that of paclitaxel but did not outperform palitaxel’s overall tumor-suppressing activities in the animal model [68][7].

6. Inhibition of Tumor Invasion and Metastasis

A common feature shared among malignancies is their ability to spread throughout an organism and colonize different sites. Cancer cells are subjected to various molecular and genetic modifications that allow them to migrate and conform to new distant microenvironments [2][1]. Considering that the metastatic potential of tumors is a major contributor to the lethality of cancer, it is important that this feature is targeted when developing cancer treatments [81][8]. Steroidal saponins have been shown to alleviate this hallmark of cancer by inhibiting key players in tumor metastasis and invasion. This includes Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs). The steroidal saponin protodioscin mitigates 5637 and T24 bladder cancer cell migration and invasion. This was assessed using a wound-healing assay, motility assay, and a transwell Matrigel invasion assay. Since EMT is linked to the metastatic abilities of cancer cells, associated proteins were evaluated in a Western blot. The results indicated a downregulation in N-cadherin and an upregulation in E-cadherin protein expression, confirming the inhibition of tumor metastasis [43][9]. The steroidal saponin A-24 inhibited the migration of gastric cancer cell lines. p53-deficient KATO-III cells and p53 wild-type gastric cancer cells were utilized in this restudyearch to determine the role of p53 in cancer cell migration and invasion. The downregulation of MMP-2 expression and a reduction in transwell migration and wound closure rates were observed in a dose-dependent manner. These results were independent of p53 status [21][10]. Bufalin prevented cancer cell invasion and migration in the gallbladder cancer cell line GBC-SD according to transwell migration and invasion results. It also lowered the expression of Snail and MMP9 while increasing the E-cadherin levels. Since cancer stem cells promote metastasis, stemness marker proteins CD133, CD44, Sox2, Oct4, and Nanog were assessed. The expression of these proteins was almost diminished after bufalin treatment [25][11]. Trillin derived from Trillium tschonoskii prohibited the migration and invasion of the liver cancer cell lines HepG2 and PLC/PRF5, as indicated in a wound healing assay. Genes involved in cell migration and invasion were suppressed after trillin treatment, as confirmed by Western blot and qPCR results. A significant reduction in the expression of STAT3, MMP1, MMP2, MucI, and VEGF was observed. This restudyearch suggested that trillin mainly targets STAT3, which is responsible for the expression of genes encoding for proteins with significant roles in the migration and invasion of tumor cells [47][12]. The total steroidal saponins from Paris polyphylla (PPSS) were shown to limit the migration and invasion of A549 cells. This was evaluated by Matrigel invasion chamber and wound-healing assays. PPSS suppressed the expression and activity of the metalloproteinases MMP-2 and MMP-9, as indicated by Western blot and gelatin zymography results [82][13]. Major constituents of PPSS included polyphyllin I, polyphyllin II, and polyphyllin E. Polyphyllin I restricted the proliferation and invasion of the cisplatin-resistant gastric cancer cell line SGC7901/DDP via the modulation of the CIP2A/PP2A/Akt pathway. CIP2A plays an essential role in tumor metastasis and EMT and its upregulation is often observed in gastric cancer. Polyphyllin I also decreased tumor volume and CIP2A, phospho-Akt, and vimentin expression in a xenograft murine model [58][14]. These results were consistent with the treatment of prostate cancer with polyphyllin I in vitro and in vivo [60][15]. It was also reported that polyphyllin I inhibited the migration of the osteosarcoma cancer cell lines 143-B and HOS in a wound-healing assay and a xCELLigence RTCA DP system. This inactivation of EMT is ascribed to the polyphyllin I-mediated inhibition of Wnt/β-catenin signaling [59][16]. Polyphyllin II suppressed tumor cell motility, as observed in wound-healing assays. It also reduced cofilin activity and MMP2, and MMP9 expression in the liver cancer cell lines HepG2 and BEL7402. This inhibition of tumor cell motility was achieved as polyphyllin II targets Akt/NF-kB signaling [49][17]. These effects were comparable to the treatment of ovarian cancer cell lines SK-OV-3 and OVCAR-3 with polyphyllin E. MMP2 and MMP9 were downregulated primarily via the inhibition of the Akt/NF-kB pathway post-polyphyllin E treatment [51][18]. In another study, polyphyllin II inhibited the migration of T24 and 5637 bladder cancer cells in a wound-healing assay. It significantly decreased N-cadherin, MMP2, MMP9, and other EMT-associated proteins to a level resembling that of normal cells [50][19].

7. Inhibition of Abnormal Metabolism

Considering the rapid growth and proliferation of cancer cells, an increased demand for energy is required to sustain such processes. Therefore, cancer cells must rewire their metabolic programs to meet these high demands. However, this metabolic reprogramming of cancer cells poses a paradox since relatively inefficient glycolysis is the preferred mode of energy production for cancer cells, even under aerobic conditions. The term “aerobic glycolysis” is used to describe the glucose metabolism of cancer cells even in the presence of oxygen. This phenomenon is known as the Warburg effect [2][1]. It is important to note that in instances of glucose deprivation, cancer cells resort to mitochondrial metabolic pathways rather than aerobic glycolysis to meet their energy demands. The modulation of both of these metabolic pathways may be a more effective approach to terminating cancer cells [83][20]. The steroidal saponin gracillin was found to inhibit both aerobic glycolysis and OXPHOS in H460 and H226B NSCLC cells, thereby depriving tumor cells of all modes of ATP synthesis [38][21]. The anti-glycolytic effects of the steroidal saponin were confirmed by the modulation of metabolites involved in glycolysis, a decrease in lactate production, and the extracellular acidification rate following the gracillin treatment. The same results were observed in triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. The downregulation of the mitochondrial function and consequently OXPHOS was evaluated using the MTT assay. The best results were observed when gracillin was combined with the OXPHOS-mediated energy production inhibitors antimycin or oligomycin [38][21]. Dioscin demonstrated inhibitory effects on glycolysis in the colorectal cancer cell lines DLD1, HCT116, SW480, HT29, HCT8, and SW620 [29][22]. The protein Skp2 is overexpressed in colorectal cancers and is important for glycolysis to take place. It also promotes the expression of Glut1 transporters, which are essential for the increased influx of glucose into cancer cells to compensate for the low yield of ATP from aerobic glycolysis [84][23]. Dioscin markedly reduced glycolysis by attenuating phosphorylated Skp2 levels in the colorectal cancer cell lines. The effects of dioscin were further investigated in a xenograft model in which the expression of Skp2 was also reduced [29][22]. A notable characteristic of the Warburg effect is the cellular utilization of glutamine as an energy source and as a precursor for the synthesis of cellular components [85][24]. Dioscin was reported to interfere with D-glutamine metabolism in a SW480 rectal cancer cell line. Aerobic glycolysis is characterized by an increase in lactic acid production as pyruvic acids are converted into lactic acids. Dioscin also downregulated L-lactic acid levels in the same cancer cell line, suggesting the inhibition of aberrant pyruvate metabolism [86][25].

8. Inhibition of Angiogenesis

Angiogenesis is the formation of new blood vessels from pre-existing vasculature. In normal tissue, this progress occurs in a transient manner under specific physiological conditions. Contrarily, angiogenesis occurs perpetually in tumors to avoid cancer dormancy and to ensure that an adequate supply of oxygen and nutrients is continuously attained. Pro-angiogenic ligands such as vascular endothelial growth factors (VEGF) and fibroblast growth factors (FGF) are overly expressed in many cancers [2][1]. Currently, anti-angiogenic drugs such as sorafenib and pazopanib are in clinical use [88][26]. Therefore, the discovery of natural angiogenic inhibitors is a sound strategy for cancer treatment. Paris saponins (PS) I, II, VI, and VII exhibited anti-angiogenic effects on HUVEC cells in a dose- and time-dependent pattern. According to MTT assays and tubule generation experiments testing the anti-cancer effects of the four steroidal saponins, PSI had the most potent inhibitory and anti-angiogenic effects. Therefore, PSI was selected for Western blot analysis. The results verified that PSI inhibited VEGFR2 phosphorylation in HUVEC cells. Additionally, the activation of proteins that are involved in the VEGFR2 pathway, including PI3K, Akt, mTOR, and S6K, was inhibited following the PSI treatment. PSI also activated p38, SRC, and eNOS, thereby changing vascular permeability and preventing angiogenesis [40][27]. The steroidal saponin terrestrosin D was tested on HUVECs and bladder-derived normal human microvascular endothelial cells to evaluate the anti-angiogenic capabilities of the compound. Terrestrosin D caused a halt in the growth of these cells in a dose-dependent manner. This inhibitory effect was further assessed in a PC-3 xenograft mouse model. Anti-CD31 antibody staining was employed to stain the tumor sections. The results indicated a notable inhibition of tumor angiogenesis in vivo following the terrestrosin D treatment. However, the steroidal saponin failed to reduce VEGF levels in the prostate cell line PC-3. Contrarily, the compound increased VEGF expression, which may be counteracted by anti-VEGF antibodies to extenuate the anti-cancer efficacy of terrestrosin D [67][28].

9. Anti-Tumor Immune Response Activation

A major hallmark of cancer is the ability of cancer cells to evade immune destruction. Tumor cells acquire this capability by downregulating antigens that are recognized by immune cells, making tumors undetectable under immune surveillance [2][1]. Steroidal saponins have been shown to induce an immune response against tumor cells that are otherwise undetectable. The steroidal saponin taccaoside A has demonstrated immunomodulatory effects in a T-cell and lung cancer H1299-GFP cell co-culture system. It regulated both CD4+ and CD8+ T-cells, leading to the lysis of tumor cells. Granzyme B (GZMB), an enzyme involved in the cytotoxic activities of T-cells, increased following the taccaoside A treatment. The same results were also observed for triple-negative breast cancer and melanoma, including anti-CTLA-4 therapy-resistant type melanoma. An in vivo mouse model confirmed the anti-tumor effects of taccaoside A, resulting in improved survival and a significant reduction in tumor size. It was also highlighted that taccaoside A activated the mTORC1/Blimp1 signaling pathway in T-cells, which enhanced their cytotoxic activities. This restudyearch suggests that taccaoside A could be a potential immunomodulatory anti-cancer agent, especially in patients that acquired resistance to other types of treatments [45][29].

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