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Oncology
Despite improvements in standardized screening methods and the development of promising therapies for colorectal cancer (CRC), survival rates are still low. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC.
- colorectal cancer
- therapy resistance
- drug repurposing
1. Repurposing Approved Drugs in Colon Cancer
Drug repurposing or repositioning involves using approved drugs for conditions different from their original indication [13,14,15]. Several drugs have acquired additional use in the past years and have been reintroduced into practice fueled by this phenomenon. For instance, thalidomide, discontinued from its original use as an antiemetic, is currently used for multiple myeloma [16] and moderate to severe erythema nodosum leprosum [17]. Another example is Sildenafil which preserves both its primary indication for erectile dysfunction [18] and repurposed indication as a treatment option for idiopathic pulmonary hypertension [19].
Drug repurposing has regained a significant role as a convenient, fast, and relatively safe drug development strategy. New drug development usually takes around 10–15 years on average [20], with a success rate reported from 2 to 10% [21,22]. According to the U.S. Food and Drug Administration (FDA), as of 2018, the compound percentage of drugs reaching stage 4 clinical trials was around 6% [23]. Drug repurposing offers significantly shorter development times and lower investments described as 160 million times lower, particularly costs regarding safety testing, molecular characterization, safety profiling, and initial marketing. It leverages known genetic, pharmacodynamic, pharmacokinetic, and adverse effect profiles, usually bypassing stage 1 clinical trials [24]. Therefore, this approach represents a more cost-efficient, expedited, and less risky strategy than traditional drug development [21].
Many successful reintroductions and alternative indications second repurposing as a feasible option in many areas of medicine. Aspirin, for example, has acquired a wide range of indications, ranging from acutely therapeutic to prolonged preventative ones [14,25]. The cardiovascular field further illustrates this diversity with the recent supportive evidence of SGLT-2 inhibitors, initially approved for hyperglycemia management, for heart failure management regardless of the patients’ ejection fraction and notwithstanding their diabetes status [26,27,28,29]. Therapeutics for Alzheimer’s disease have been highly reliant on this strategy. Since memantine in 2003, no new drugs had been approved until the FDA granted the recent fast track concession for aducanumab in 2021 [14,30]. As of 2017, approximately 27 FDA-approved drugs were being evaluated for Alzheimer’s disease in stages 1–3 clinical trials [14].
Oncology has also gained benefits from drug repurposing. Estimation is that 5% of the anticancer drugs entering phase 1 clinical trials are eventually approved [31]. Certain calcium channels blockers such as felodipine and amlodipine besylate undermine filopodia stability in cancer cells, decreasing the likelihood of progression, invasion, and metastasis [32]. Metformin, classically an antidiabetic drug, has been described to decrease tumor growth. Although metabolic reprogramming halting oxidative phosphorylation and multi-targeted mTOR inhibition have hypothesized metformin’s antitumoral activity, precise mechanisms remain obscure [21,33,34].
The benefits of drug repurposing are evident after their serendipitous discovery and raise interest in predictive tools to optimize outcomes. Many approaches group together into either experimental or computational models [24,35]. The former usually involves either in vitro analysis measuring affinity and interaction stability, also called binding assays, or combined in vitro/in vivo models using compound libraries to test for cellular lineage changes, known as the phenotypic model. The phenotypic approach aims to reproduce diseases in an experimental cellular environment and relies on known compound libraries to test and characterize cellular responses [24]. Alternatively, known compounds have been assessed using in silico models stemming from structure-based principles: direct molecular docking, inverse molecular docking, and receptor-based pharmacophore searching [36]. Drug-based strategies use established drug information such as pharmacodynamics, biochemical, adverse effect profiles, and genomic data to determine potential alternative uses. Transcriptomics data are especially valuable to depict deviant cellular responses to diverse pathologic states, notably those with solid genetic pathomechanisms. Conversely, knowledge-based strategies use well-characterized molecular disease mechanisms to depict candidates for drug repurposing [35].
Large genetic and disease datasets are becoming publicly available, and computational tools for processing massive data are evolving accordingly. Computational-based drug repurposing uses data mining, machine learning, and network analysis to distill large datasets involving disease-specific transcriptomics, proteomics, drug efficacy, responses, and even clinical variables [35]. This information provides insight into complex biologic processes such as epigenetic regulation in cancer cells. Furthermore, drug repurposing approaches may be used for epigenetic reprogramming of cancer cells to increase susceptibility via differential transcriptome expressions. A study characterized 45 FDA-approved drugs yielding synergistic activity with histone deacetylating agents and methylation inhibitors. Additionally, they characterized 85 FDA-approved medications that antagonized the action of these drug families, thwarting favorable responses in colon cancer cells. Altogether, these findings illustrate the benefits and complexity of drug repurposing to design personalized and highly effective treatment plans that account for previously unknown drug interactions [37].
2. Anti-Hypertensives and Anti-Arrhythmic Drugs
Angiotensin I converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly used drugs that have life-prolonging effects on patients treated for several diseases including but not limited to hypertension and heart failure [90]. An in vivo study by Kubota et al. suggested that both ACEIs and ARBs suppress colitis-induced CRC by decreasing chronic inflammation and oxidative stress in obese mice [38]. In another study by Kedika et al., patients who had one or more histologically confirmed adenomatous polyps on an index colonoscopy and received lisinopril—an ACEI—had a 41% reduction in the risk of developing similar polyps over the next 3–5 years [39].
Beta blockers (BB) are class II antiarrhythmic drugs used primarily to treat cardiovascular diseases and many other conditions [91]. In a study by Tapioles et al., Nebivolol was shown to selectively inhibit mitochondrial respiration in an HCT-116 colon cancer cell line by decreasing the activity of complex I of the respiratory chain and restraining the growth of colon cancer cells, hinting towards a repurposing potential for this drug in colon cancer [40]. Furthermore, Engineer et al. demonstrated that the combination of ACEI/ARB with BB was associated with increased survival, decreased hospitalization, and decreased tumor progression in advanced CRC [92].
3. Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) employ their anti-inflammatory, analgesic, and antipyretic properties by inhibiting the cyclooxygenase (COX) enzymes [93]. COX-2 overexpression is a major risk factor for the development of CRC [94]. The therapeutic effect of aspirin in CRC can be explained by inhibition of COX-2 as well as the c-MYC transcription factor [41,42]. Furthermore, aspirin blocks platelet activity which is implicated in cancer metastasis and immune evasion [43]. However, Chan et al. argued that aspirin must be used for more than 10 years to achieve a statistically significant reduction in COX-2 positive cancer [44].
Celecoxib works by selectively and reversibly inhibiting COX-2, and thus acts to decrease inflammation and pain without affecting platelets [95]. Many studies concluded that celecoxib increases radiosensitization of CRC cells [96,97]. Celecoxib also affects p53 by regulating the expression of p21 and CyclinD1 in a COX-2-independent manner, by upregulating BCCIP, increasing radiosensitivity in the HCT116 CRC cell line [45]. A randomized controlled trial by Bertagnolli et al. showed that celecoxib was effective for the secondary prevention of colorectal adenomas and decreased the cumulative incidence of adenomas after 3 years from 60.7% in the placebo arm to 43.2% in patients receiving 200 mg of celecoxib twice daily [46].
4. Anti-Hyperlipidemic Drugs
Statins markedly inhibit HMG-CoA reductase, the enzyme that controls the rate-limiting step in the cholesterol synthesis pathway in the liver [98]. Remarkably, in a large study including 1953 patients with CRC and 2015 controls, the use of statins for at least 5 years was associated with a significantly reduced relative risk of developing CRC (odds ratio (OR) = 0.50; 95% confidence interval (CI), 0.40–0.63) [99]. In vivo, lovastatin was shown to restrict cancer progression and metastasis formation by inhibiting MACC1 [47]. In a large meta-analysis including a total of 31 studies and involving more than 1.6 million subjects, statins were shown to have a moderate protective effect against developing CRC [48].
5. Anti-Diabetic Drugs
Metformin, an oral anti-diabetic medication used for type 2 diabetes mellitus, is a biguanide drug that increases insulin sensitivity, decreases intestinal absorption of glucose, and decreases its production by the liver [100]. Previous studies have shown a protective effect of metformin in CRC risk and prognosis [101,102]. The current understanding is that metformin inhibits the mammalian target of rapamycin (mTOR) pathway which plays a central role in CRC cell growth and proliferation [49]. Furthermore, metformin downregulates IGF receptor activation through decreasing insulin and insulin growth factor, resulting in decreased proliferation in colorectal neoplasia [103,104]. Inhibition of mTOR is achieved through inhibition of mitochondrial mammalian respiratory chain complex I followed by activation of liver kinase B1 and downstream target Adenosine monophosphate-activated protein kinase (AMPK) [50,51]. Other research has shown that metformin, through modulation of oxidative stress and nuclear factor-κB (NF-κB) inflammatory responses would induce apoptosis in CRC cell lines [52,53]. Metformin may also increase sensitivity of cancer cell lines to chemotherapeutic agents such as 5-Fluorouracil, irinotecan, and paclitaxel [105,106,107].
Dapagliflozin, another oral antihyperglycemic medication used for type 2 diabetes mellitus works by inhibiting the sodium/glucose cotransporter 2 (SGLT2) in the proximal tubules of the kidney [108]. Dapagliflozin decreases the adhesion of CRC cells by affecting cellular interaction with Collagen types I and IV through activating ADAM10, which subsequently causes a loss in the full-length DDR1 [54]. DDR1 binding to Collagens I and IV is necessary to stimulate cell–collagen interactions [109]. Dapagliflozin also decreases colon cell proliferation by increasing Erk phosphorylation in the HCT116 human colon cancer cell line [55]. In a case report by Okada et al., SGLT2 inhibition in combination with the EGFR inhibitor, cetuximab, reduced both tumor size and carcinoembryonic antigen (CEA) levels in CRC with liver metastasis [110].
6. Anti-Helminthic Drugs
Mebendazole is a broad spectrum benzimidazole that inhibits microtubule synthesis by blocking tubulin polymerization [111]. Mebendazole has cytotoxic activity against different CRC cell lines such as HCT-116, RKO, HT-29, HT-8, and SW626 [56,112]. Nygren and Larsson reported that mebendazole induced remission of metastatic lesions in a patient with refractory metastatic CRC [113]. Another study carried out on mice with a constitutional mutation in the Adenomatous polyposis coli (APC) gene showed that the combination of mebendazole and sulindac (an NSAID) decreased both the number and size of intestinal microadenomas by inhibiting MYC and COX-2 pathways, angiogenesis, and the release of pro-tumorigenic cytokines [57].
Niclosamide is a salicylamide derivative that acts by uncoupling oxidative phosphorylation and regulating different signaling pathways [114]. Niclosamide downregulated the Wnt/β-catenin cascade, which is aberrantly activated in 80% of sporadic CRC [115], in both in vitro and in vivo studies [58] and resulted in decreased proliferation in multiple human CRC cell lines such as HCT-116, Caco2, and HT-29 [59], possibly via the induction of autophagy [116]. Furthermore, a recent study by Kang et al. demonstrated that niclosamide could be combined with metformin to synergistically inhibit APC-mutant CRC by suppressing Wnt and YAP [117].
7. Anti-Retroviral Drugs
Tenofovir is a nucleoside antiretroviral drug that acts by inhibiting the reverse transcriptase enzyme [118]. Tenofovir also inhibits the activity of human telomerase [119], a crucial enzyme for tumorigenesis and cancer proliferation, whose inhibition represents a promising therapeutic strategy in cancer treatment [120,121]. Sherif et al. demonstrated that rats receiving tenofovir at a dose of 50 mg/kg for 24 weeks had diminished colorectal cell proliferation attributed to decreased Bcl-2 and cyclin D1 expression [60]. Zidovudine, also known as azidothymidine, is another nucleoside reverse transcriptase inhibitor (NRTI) used in the treatment of human immunodeficiency virus (HIV) [122]. Brown et al. demonstrated Zidovudine’s telomerase inhibition activity in the HT-29 colon cancer cell line [61]. Furthermore, Fang et al. showed that the antitumor activity of zidovudine in colon cancer cells is mediated by increased expression of the p53-Puma/Bax/Noxa pathways favoring apoptosis, and activation of the p53-p21 pathway promoting cell cycle arrest [62]. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV that is selectively cytotoxic to different tumor cell lines, including colorectal carcinoma, by activating the phosphorylation of p53 [63].
Protease inhibitors (PI) are also drugs that suppress the action of HIV proteases to inhibit viral growth, infectivity, and replication [123]. Indinavir and Saquinavir are PI that suppress the growth of human tumor cells by blocking angiogenesis and matrix metalloproteinases to inhibit tumor invasion and progression. [64]. Furthermore, Mühl et al. reported that Ritonavir synergizes with butyrate to induce apoptosis of CRC cells [66]. The anticancer effect of Ritonavir is most likely due to the inhibition of proteolytic degradation, which causes the accumulation of p21 [68], the decreased production of TNF-α, IL-6, IL-8, and VEGF [67], and the increased expression of anti-inflammatory heme oxygenase-1 [66].
Integrase inhibitors are the latest class of antiretroviral drugs which were approved for HIV therapy due to their efficacy, tolerability, and safety [124]. Raltegravir is an integrase inhibitor that inhibits the Fascin-1-dependent invasion of colorectal tumor cells in vitro and in vivo [69]. Fascin-1 is an actin cross-linking protein whose elevated expression is associated with aggressive clinical progression, dismal prognosis, increased recurrence, and worse survival outcomes in patients with CRC [125,126].
8. Anti-Microbials
Other anti-microbial drugs have been investigated for repurposing in colon cancer treatment including doxycycline, a semi-synthetic antibiotic derivative of tetracycline used in the treatment of a wide variety of infections [127]. Doxycycline has also been shown to inhibit matrix metalloproteinases [128]. Onoda et al. demonstrated that a combination therapy consisting of doxycycline and a COX-2 inhibitor suppressed colon cancer cell proliferation and invasion [71]. Doxycycline reportedly induced apoptosis in a dose-dependent manner through activation of caspases, release of cytochrome C, and translocation of Bax [70].
Another antibiotic with potential in cancer therapeutics is clarithromycin. Clarithromycin is a potent inhibitor of tumor-induced angiogenesis [73] showing increased efficacy when combined with approved anticancer drugs [72,75,129]. It is also implicated in attenuating autophagy in myeloma cells [130]. Targeting autophagy is considered a promising strategy for colon cancer therapy [131,132]. In a study by Petroni et al., clarithromycin was indeed shown to modulate autophagy in human CRC cells and inhibited the growth of tumors by targeting hERG1 [74].
The inhibition of autophagy as a mechanism of anticancer activity is also shared by azithromycin, another macrolide antibiotic [76,77]. Qiao et al. demonstrated that azithromycin had a synergistic antitumor activity with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in colon cancer cells. Azithromycin may also suppress autophagy by upregulating the expression of p62 and LC-3B to ultimately induce colon cancer cell death [78].
Gemifloxacin is a fluoroquinolone used in the setting of community-acquired pneumonia and acute exacerbations of chronic bronchitis [133]. Kan et al. demonstrated that gemifloxacin inhibits the migration and invasion of SW620 and LoVol colon cancer cells and downregulates Snail to reduce epithelial-to-mesenchymal transition (EMT). Gemifloxacin also suppresses the NF-κB pathway and cytokine-mediated cell migration and invasion as shown by decreased levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor (VEGF) [79].
Antimalarials are also being considered for the treatment of colon cancer. Artesunate is an antimalarial agent recommended for the treatment of patients with severe Plasmodium falciparum malaria [134]. In a preclinical model of CRC, artesunate was found to suppress inflammation and oxidative stress [81]. Efferth et al. demonstrated a cytotoxic action of artesunate on tumor cells via both p53-dependent and -independent pathways [135] implicated in downregulation of β-catenin [80]. Mefloquine, another antimalarial drug, was found to induce growth arrest and apoptosis of CRC cells in mice via inhibition of the tumor NF-κB signaling pathway [82].
This entry is adapted from the peer-reviewed paper 10.3390/cancers14092105
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