Co-Adjuvant Drugs in Cancer Therapy: History
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Contributor:
Laurentia Gales
,
Leyla Forsea
,
Diana Mitrea
,
Irina Stefanica
,
Irina Stanculescu
,
Radu Mitrica
,
Mihai Georgescu
,
Oana Trifanescu
,
Rodica Anghel
,
Luiza Serbanescu

Repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.

  • cancer therapy
  • metformin
  • mebendazole
  • atorvastatin
  • propranolol
  • beta-adrenergic receptors
  • drug repurposing

1. Introduction

Prognoses are still dismal for advanced-stage cancer patients, despite the regular introduction of new molecules after lengthy clinical trials. Each case will go through a complex combination of surgery, radiotherapy, and chemotherapy following the decision of a multidisciplinary tumor board. Over the years, in oncology research, there has been growing evidence on the use of repurposed agents such as antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, and antidiabetic agents [1]. They have well-known properties and toxicity profiles, making them feasible for rapid implementation in new medical applications. In this entry, researchers aimed to provide a scientific rationale for the use of metformin, mebendazole, atorvastatin, and propranolol as potential valuable co-adjuvants in cancer treatment. Frequently, for nonmalignant-associated pathologies, a combination of two or even three of the abovementioned drugs are present in the daily administration schedule of a given patient, throughout months or years of cancer therapy. Researchers' patients’ desperate search for alternative cancer therapy often translates into the empiric use of drugs that they have within reach, with minimal scientific background. This entry highlights the latest observational and preclinical data in the search for antitumor effects and the few clinical attempts to augment the oncological treatment with one of these four drugs of interest.
Metformin, a biguanide antihyperglycemic agent, is the most widely used first-line treatment for type 2 diabetes [2]. Thus, for many years it has been administered in diabetic patients bearing all other associated comorbidities including cancer. The common dosage is 500–2000 mg/day for its antidiabetic indication. The role of metformin has grown in recent times because of the vast number of epidemiologic studies that have been conducted on its potentially positive effects in decreasing cancer incidence and mortality. Significant benefits have been found, especially in diabetic patients with early-stage colorectal cancer and early-stage prostate cancer, often relating to an increased response to radiotherapy [3][4].
Mebendazole is an FDA-approved benzimidazole with a good safety profile, which has been widely used to treat parasitic diseases, mainly due to the fact of its tubulin binding capacity and prevention of microtubule polymerization. As an anthelmintic, common presentation of mebendazole is in 100 mg tablets, with indications for 100 mg as a single dose to 100–200 mg/day. Its mechanism of action has been linked to in vitro antiproliferative activity against cancer cells [5], but preclinical anticancer research also identified its ability to bind and inhibit signaling of selective tyrosine kinases including VEGFR2, TNIK, and BRAF [6]. It crosses the blood–brain barrier and evidence supports the use of mebendazole for both therapeutic and preventive purposes in the treatment of brain and colon cancers. [7][8]. Mebendazole is now being tested in clinical studies for glioblastoma, pediatric brain tumors, colon cancer, pancreatic cancer, thyroid cancer, prostatic cancer, and breast cancer [9][10][11].
Atorvastatin is a member of the statin family that inhibits HMG-CoA reductase activity, thus reducing cholesterol levels through inhibition of the mevalonate pathway at daily doses between 40 and 80 mg. It exhibits anticancer activity in several human cancer cells, mainly due to the fact of its autophagy-inducing effect [12][13][14][15]. On the other hand, several studies demonstrated the radioprotective effect of atorvastatin on normal tissues [16][17][18].
Various antihypertensive drugs influence the evolution of cancer such as calcium channel blockers, which stimulate apoptosis in the myeloma cell line and an autophagy-like process in prostate and colon cancer; angiotensin receptor blockers and their role in the upregulation of antitumoral T-cell lines; angiotensin-converting enzyme inhibitors revealing evidence of the downregulation of VEGF transcription. Beta-adrenergic receptors have been associated with signals involved in tumor evolution [19]. As a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors, propranolol was one of the first beta-blockers used in cardiology for arterial hypertension control, dysrhythmias, migraines, anxiety-associated symptoms, with daily doses of approximately 80 mg/day. It is also used in vascular tumors, such as infantile hemangiomas, but growing evidence suggests an emerging role in the treatment of vascular sarcomas [20]. 

2. Metformin

Even though metformin has a long history of being used as an antidiabetic drug (derived from the plant Galega officinali), its mechanism of action was only recently discovered [21]: a direct one via the inhibition of mitochondrial ETC/OxPhos and the consequent activation of AMPK [22]; an indirect mechanism by lowering systemic insulin levels (via inhibition of hepatic gluconeogenesis) [21][23].
The rationale behind metformin’s proposed antitumor effect:
  • Insulin stimulates cellular proliferation, and multiple signaling pathways are activated after insulin receptors or IGF-I receptors interact with their ligands; lowering insulin levels in the host blood removes one of the tumor-stimulating pathways [3][24];
  • Metformin stimulates cancer cell apoptosis through activation of the AMPK/LKB1/TORC1 signaling pathway and inhibition of mTOR activity;
  • Metformin counteracts metabolic disturbances known to influence tumor behavior such as obesity and insulin resistance. Other important factors are metformin’s anti-inflammatory effects;
  • Metformin increases tumor radiosensitivity through mitochondrial ETC inhibition of oxygen consumption, thus improving tumor oxygenation;
  • Metformin increases tumor radiosensitivity through the downregulation of the EGFR/PI3K/Akt signaling pathway, which further leads to mTOR inhibition, cell cycle arrest, and repression of colony formation ability [4][25][26].
Observational studies revealed that diabetic patients treated with metformin had a lower incidence of any kind of cancer in a dose-dependent manner compared to patients on other treatments. Coyle et al. conducted an analysis of 27 observational studies (24,178 participants), and the results regarding the tumor-related efficiency of metformin were mixed. A more beneficial approach for diabetic patients with prostate cancer may come from radical radiotherapy combined with metformin, whereas for early-stage colorectal cancer, metformin provided a clear benefit [3].
As shown in a complex study conducted by Zanella et al., first an in vitro analysis of various carcinoma cell lines revealed a significant decrease in oxygen consumption after metformin treatment, with the prostate cell line, LNCaP, being the most metformin-sensitive. This result represents an alternative method to improving tumor oxygenation for higher radiosensitivity. Second, mice bearing xenografts that were administered metformin 30 min before irradiation (100 mg/kg metformin equivalent to approximately 25% of the daily oral dose taken by patients with diabetes) revealed an improved oxygenation of the tumor and improved in vivo response to radiotherapy. In the same study, a retrospective clinical analysis of 504 prostate cancer patients identified 114 patients taking metformin (dosage not available) at the time of radiotherapy. For these patients, metformin use was a significant and independent factor reducing early biochemical relapse after radiotherapy [4].
Regarding advanced prostate cancer, neo-adjuvant radiotherapy is usually successful, but radioresistance is a key issue in many patients. In Zhang’s study, the investigators researched the effect of metformin on tumor cell radiosensitivity in prostate cancer. Using clonogenic survival assays, the team discovered that metformin enhanced radiosensitivity in prostate cancer cells. Moreover, there was an increase in radiation-induced tumor growth delay in mice with irradiated subcutaneous tumors. Additionally, mice with subcutaneous tumor implants had a longer life span after the combination of metformin and radiation. The reduced phosphorylation of DNA-PKcs caused by the downregulation of the EGFR/PI3K/Akt signaling pathway was essential for metformin to induce radiosensitivity in prostate cancer cells [27].
Iliopoulos et al. found metformin in combination with doxorubicin worked better than either drug alone at blocking prostate cancer growth as well as inhibiting relapse in mouse xenograft models. Because of this, doxorubicin doses can be lowered with milder toxicity from this medication with better tolerability and results. Similar results concerning the above combination were also seen in breast cancer cells with metformin plus a variety of chemotherapeutic agents (i.e., paclitaxel, carboplatin, and doxorubicin) [28]. This type of regimen has been seen to prevent relapse in xenografts generated with multiple types of breast cell lines. CSCs are a subset of tumor cells that are resistant to many anticancer treatments and are able to self-renew and regenerate various cell types that make up a tumor [29]. Prostate cancer stem cells are resistant to many of the usual cancer therapies, and it is believed that they contribute to local invasion and bone metastasis [30]. Underlying the fact that metformin selectively kills CSCs, researchers genetically manipulated human breast epithelial cells to enrich for stem cells and tested these together with three distinct breast tumor cell lines [31]. They discovered that metformin is selectively toxic to CSCs. To test metformin’s action in vivo, mice were implanted with transformed mammary epithelial cells and treated with three cycles of metformin and with doxorubicin. In this combination, metformin erased the tumors and prevented recurrence. No CSCs were recovered after the treatment and this response was sustained for approximately two months. The results were poorer when using only one agent, as metformin had no antitumor effect and doxorubicin revealed only an initial tumor shrinkage followed by relapse [32].
Type 2 diabetes is associated with increased incidence of colorectal cancer because of the hyperglycemic characteristic of the cancer cells, which require high glucose usage to compensate for the high metabolic activity [33][34]. A recent study concerning diabetics with stage of I to III colorectal cancer, who take metformin versus non-metformin diabetics, revealed a lower mortality in the first category [35]. The overall survival among patients with colorectal cancer and type 2 diabetes, who took metformin (dose not available), was better than patients who did not take this antidiabetic [36], but other authors recommend caution in interpreting these results—studies developed within an exclusive diabetic population may be biased due to the differences in the severity of diabetes between better prognosis populations with a first-line metformin approach and patients receiving other non-metformin antidiabetics [37]. However, for patients with thyroid carcinoma, it is not just the severity of associated morbidities that influences prognostics but also the direct relationship between the high glucose environment and the metformin’s antitumor effect. Metformin in a high-glucose environment inhibited cell proliferation and induced cell death in a low-glucose environment; therefore, the authors simply increased the cell sensitivity to metformin by adding a glycolysis inhibitor [38].
Many in vivo studies have been conducted to investigate the benefits of metformin, and the results are promising in regard to the growth of intestinal polyps. In mutated mice, high-dose metformin treatment for 10 weeks (250 mg/kg/day) inhibited the size of polyps but not the total number of intestinal polyps [34]. Given that many of the reports of metformin being used in the treatment of colorectal cancer are mostly centered among diabetic patients, researchers cannot safely say that it is, indeed, beneficial for nondiabetic patients too. The follow-up periods in the studies regarding colorectal cancer were very short; therefore, clinical studies that focus on late stages of colorectal cancer with patients using metformin for a longer period of time would offer a better view of the protective effect of metformin [34].
High-grade gliomas, especially glioblastomas, are among the most aggressive primary tumors that mandate the urgent development of new therapies to increase the efficacy of radio/chemotherapy. In vitro studies using metformin reported decreased proliferation, cell cycle arrest, autophagy, apoptosis, and cell death with a concomitant activation of AMPK, Redd1, and inhibition of the mTOR pathway [39].
Lately, clinical trials on the use of metformin in oncology have begun to report results. One of the very few randomized clinical trials on this topic, the OCOG-ALMERA, enrolled patients with locally advanced lung cancer for metformin at 2000 mg/day during chemoradiotherapy and afterwards for up to 12 months. With only 54 randomized patients, the study stopped early due to poor accrual. The results revealed worse local control and increased side effects associated with metformin use [40].
Another lung cancer trial, an open-label phase 2 study, NRG-LU001, enrolled 167 nondiabetic patients with unresectable stage 3 non-small cell lung cancer to receive carboplatin and paclitaxel-based chemoradiation either alone or with metformin (2000 mg/day after a gradual increase over 2 weeks, from 1000 mg/day in the first week). Interestingly, the study team reported an unexpected better 1-year PFS in the control arm than the one achieved in the PACIFIC reference study with durvalumab after chemoradiotherapy. However, the metformin arm, although well tolerated, did not bring any significant differences in the rates of survival, locoregional recurrence, or distant metastasis [41].
The largest clinical trial concerning metformin use, MA. 32, was a phase 3, double-blind trial that enrolled 3649 nondiabetic patients, with high-risk nonmetastatic, operable, breast cancer, randomized to receive standard therapy in association either with metformin at 850 mg twice a day or a placebo. Again, for most of the patient subcategories, there were no significant differences in disease-free survival and mortality. Grade 3 nonhematological toxic events, such as hypertension, irregular menses, and diarrhea, occurred more frequently in patients taking metformin than in patients taking the placebo. A subsequent analysis revealed beneficial results only for a small subset of patients (17% of the total) who had a HER2-positive disease. This subgroup presented better disease-free survival and lower mortality with metformin use vs. a placebo. The benefits seen in this HER2-positive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant [42].

3. Mebendazole

The most common presentation of mebendazole is in 100 mg tablets. As an anthelminthic with low-dose administration, side effects usually consist of abdominal pain and discomfort, flatulence, and diarrhea. Neutropenia and abnormal liver function tests have rarely been reported in high-dose regimens [43].
The main antitumor mechanisms of mebendazole:
  • Behaves like colchicine and chemotherapy drugs, such as taxanes and vinca alkaloids, inhibits tubulin polymerization, and causes mitotic arrest, selectively in tumor cells without major side effects [44];
  • Significantly reduces tumor angiogenesis, with no effect on microvessel density in normal tissue [8];
  • Inhibits the hedgehog pathway and Gli1, BRAF, and MEK expression, with a reduction in tumor proliferation. Higher concentrations of mebendazole determine apoptosis through phosphorylation of Bcl-2 and activation of the mitochondrial pathways. P21 and p53 pro-apoptotic proteins are elevated after mebendazole treatment;
  • Inhibits kinases, such as TNIK and VEGFR, thereby increasing tumor infiltration with CD8 T cells for better tumor control;
  • Stimulates pro-inflammatory response and a pyroptosis type of cell death through activation of the NF-κB/NLRP3/GSDMD pathway;
  • Activates an antitumor immune response through increased pro-inflammatory M1-phenotype cytokines (i.e., IL-1β, IL-8, IL-6, and tumor necrosis factor) and T-cell-attracting chemokines [43].
In vitro use of mebendazole and two other class representatives, flubendazole and fenbendazole, inhibit proliferation of glioblastoma cells in a dose-dependent manner by suppressing DNA synthesis, modulating the expression of key epithelial–mesenchymal transition markers, and inducing cell cycle arrest at the G2/M phase via the pro-apoptotic genes in the P53/P21/cyclin B1 pathway. Furthermore, the pyroptosis type of cell death, also known as cellular inflammatory necrosis, was found in the above-treated glioblastoma cells, through the NF-κB/NLRP3/GSDMD pathway. Tumor growth inhibition was confirmed, in vivo, in a nude mouse U87 cell xenograft model [45]. In a preclinical study from 2018, mebendazole was tested on rat models of glioblastoma and medulloblastoma. Even if mebendazole administered in monotherapy caused cytotoxicity, when combined with radiotherapy, colony formation was reduced even further and cleaved caspase-3 levels were higher. Both mebendazole monotherapy and the association had a survival advantage in the in vivo investigation, with an increase in apoptosis and reductions in tumor cell and vascular growth [46].
The association between temozolomide and other drugs could be an option for those patients who have resistant tumors to radiotherapy or chemotherapy (temozolomide), respectively, for those with low levels of FGFR3 and AKT2. Kipper et al. demonstrated that triple therapy with mebendazole plus topotecan plus bevacizumab versus temozolomide was superior at decreasing cell numbers in different cultures. As a result of these findings, the triple combination of temozolomide, vinblastine, and mebendazole may be a viable treatment option for gliomas with low expression of FGFR3/AKT2 [47].
Mebendazole demonstrated a decrease in breast-cancer-initiating cell levels, as it promoted double-stranded breaks, apoptosis, and arrested cells in the G2/M phase of the cell cycle [10]. Similarly, in triple-negative breast cancer cells and radiotherapy-resistant breast cancer cells, mebendazole determined DNA damage, downregulation of CD44 stem cell marker, and downregulation of OCT3/4 and ESM-1 tumor progression markers. Triple-negative breast cancer patients face short survival due to the tumor developing treatment resistance. The authors concluded that the addition of mebendazole to radiotherapy may provide a synergistic antitumor effect as part of a treatment strategy for triple-negative breast cancer [48].
Among the cancer types that mebendazole was proven against were human papillary and anaplastic thyroid carcinoma cells in vitro. By activating the caspase-3 pathway, mebendazole enhanced the percentage of cells in G2/M cell cycle arrest, triggered late-stage apoptosis in papillary (B-CPAP) and anaplastic (8505c) cell lines, decreased migratory and invasive capacity in aggressive 8505c cells. Another benefit of daily oral mebendazole was that it prevented existing thyroid cancers from spreading to the lungs and all these coupled with a known safety profile of high-dose oral mebendazole [44].
In association with anti-inflammatories, mebendazole significantly reduced tumor initiation and development in colon cancer models [49], and a similar effect was hypothesized in pancreatic cancer mice models. Both the KrasLSL.G12D/+ and the Pdx1-Cre (KC) mouse models of cerulean-induced inflammatory pancreatitis and the KrasLSL.G12D/+, Tp53R172H/+, and Pdx1-Cre (KPC) animal types of advanced pancreatic cancer responded to mebendazole administration by reducing pancreas weight, dysplasia, and intraepithelial neoplasia development. Mebendazole displayed a local, antitumor effect but also acted against liver metastases [11].

4. Atorvastatin

Tumor cell membranes contain essential phospholipids made from fatty acids, similar to healthy cells. These lipids are obtained by the endogenous metabolites through the mevalonate pathway, making the tumor dependent on this process. Furthermore, multiple tumors demonstrate increased fat uptake, storage, and production, which lead to tumor progression.
The main atorvastatin antitumor mechanisms:
  • Inhibition of cholesterol and the accompanying metabolite, 27-hydroxycholesterol, through the mevalonate pathway. The latter behaves as an estrogen receptor, important in estrogen-driven tumors;
  • Inhibition of Akt/mTOR and activation of the MAPK pathway [12];
  • Reduction of isoprenoid production, intermediate metabolites in the cholesterol pathway, which leads to a decrease in the cell-growth-stimulating proteins Ras, Rac, and Rho. Depletion of isoprenoid driven growth proteins induces apoptosis;
  • Suppression of tumor development associated inflammation through inhibition of pro-inflammatory cytokines;
  • Stimulation of autophagy and ferroptosis, associated with inhibition of the mevalonate pathway, as a type of programmed cell death, characterized by iron overload and lipid reactive oxygen species accumulation [13].
Thus, in the case of cancer patients with high amounts of lipids, the proteins involved in this process may be excellent chemotherapeutic targets [50]. Inhibiting this vital process could be beneficial in cancer cells, as they are usually rapidly proliferating without affecting too much the slower reproducing healthy cells. Inhibition of cholesterol synthesis by statins impacts cell membrane integrity, protein synthesis, cell signaling, and cell cycle progression [51].
For patients with head and neck cancer and hyperlipidemia, atorvastatin use (dose not available) improved OS and CSS compared to hyperlipidemia patients not taking atorvastatin, but this first category also recorded benefits from atorvastatin use when compared to patients without hyperlipidemia. Therefore, it is possible that statins disrupt cancer cell metabolism and proliferation without increasing cancer-related toxicity events [52]. These are radically different results from those obtained with another electron chain inhibitor, the above-described metformin, which showed far poorer results in combination with radiotherapy for lung cancer patients [40][41]. From this point of view, it would be of great interest to test atorvastatin’s antitumor effects in patients without hyperlipidemia.
There are limited studies on the effect of cotreatment with atorvastatin and radiotherapy. In a study by Hosseinimehr et al., the radiosensitizing effects of atorvastatin were evaluated by flow cytometry and antiproliferation assays for breast and lung cancer cells. The apoptosis rate of MDA-MB-231 breast cancer cells and A-549 lung cancer cells was increased in the atorvastatin group as well as in the irradiated group with a higher benefic effect recorded from a combination of both treatments. Atorvastatin increased reactive oxygen species production, thus further augmenting apoptosis in irradiated cells. An atorvastatin dose concentration of 10 µM diluted in culture medium proved a radiosensitizing effect on the above-tested tumor types and a radioprotective effect on previously irradiated normal lymphocytes [16][53].

This entry is adapted from the peer-reviewed paper 10.3390/medicina58091239

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