Antibiotics

 

Antibiotics may indirectly improve progression-free survival (PFS) among patients with metastatic renal cell carcinoma (RCC) (link)

Background:

Diarrhea occurs in ~50% patients with mRCC receiving VEGFTKIs, and is a common cause of VEGFTKI Rx dose reductions/delays/interruptions. Stool bacteroides level directly correlates with diarrhea in these patients on Rx with VEGFTKI (Pal SK, Clinical Cancer Research 2015, PMID:26152743). Hypothesis was that mRCC patients on incidental antibiotics (ABX) which also target stool bacteroides will have less diarrhea, leading to improved Rx compliance, and improved outcomes on VEGFTKI.

Results:

Among patients prescribed antibiotics with bacteroides sensitivity, the median PFS was 18 months. Patients prescribed antibiotics without bacteroides sensitivity had a median PFS of 9 months, and patients not prescribed antibiotics had a median PFS of 8 months. The authors concluded that while validation is needed, in “these hypothesis generating data, incidental targeting of stool bacteroides with [incidental antibiotics] correlated with improved PFS in [metastatic] RCC patients on [first-line VEGF-TKIs].”

Doxycycline sensitizes renal cell carcinoma to chemotherapy by preferentially inhibiting mitochondrial translation, 2021

Objectives: The anti-cancer activity of doxycycline has been reported in many cancers but not renal cell carcinoma (RCC). This study aimed to determine the efficacy of doxycycline alone and in combination with paclitaxel and analyze the underlying mechanism in RCC.

Methods: Proliferation, colony formation and apoptosis assays were performed in RCC cell lines after drug treatments. An RCC xenograft mouse model was generated, and tumor growth was monitored. Mechanistic studies focused on mitochondrial translation and functions.

Results: Doxycycline at clinically achievable concentrations inhibited proliferation and colony formation and induced apoptosis in RCC cell lines. In normal kidney cells, doxycycline at the same concentrations either had no effect or was less effective. The combination index value demonstrated that doxycycline and paclitaxel were synergistic in vitro. Consistently, this combination therapy was significantly more effective than the monotherapy in RCC xenograft mice without causing significant toxicity. Mechanistic studies revealed that doxycycline acts on RCC cells via preferentially inhibiting mitochondrial DNA translation, thereby disrupting multiple mitochondrial complexes and impairing mitochondrial respiration.

Conclusions: Doxycycline is a useful addition to the treatment strategy for RCC. Our work also highlights the therapeutic value of mitochondrial translation inhibition in sensitizing RCC to chemotherapy.

Monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis

In summary, monensin, a Na+ ionophore, efficiently inhibited the cell proliferation of renal cell carcinoma cell lines by inducing cell cycle arrest or by triggering apoptosis. These results suggest that monensin may be a useful drug in the treatment of renal cell carcinoma patients.

Monensin induces cell death by autophagy and inhibits matrix metalloproteinase 7 (MMP7) in UOK146 renal cell carcinoma cell line.

Monensin acts as antiproliferative agent, activating autophagy and downregulates PRCC-TFE3 fusion transcript in Xp11.2 translocated tumor cell line (RCC).

Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs

The data presented here clearly show that the antibiotics mentioned above should be recognised in the near future as novel agents able to eradicate cancer cells and cancer stem cells (CSCs) across several cancer types.

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.

These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients

Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study

Doxycycline was administered orally for 14 days before surgery for a daily dose of 200 mg. Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (p-value < 0.005), when compared to pre-doxycycline tumor samples. Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients in vivo.

Antibiotic may prevent breast cancer recurrence

In a recent paper now published in the journal Frontiers in Oncology, the scientists outline the potential use of an antibiotic called doxycycline to clear up CSCs. The researchers recruited just 15 participants based at the University Hospital in Pisa, Italy. They gave nine participants doxycycline each day for 14 days leading up to surgery to remove a tumor. The remaining six participants acted as a control and took no drugs. To assess whether the antibiotic had an impact on CSCs and the chance a tumor would recur, the scientists tested a number of biomarkers. They assessed these so-called measures of stemness in tumor tissue removed before the operation (core biopsies) and on tumor tissue excised during the procedure. The scientists measured a significant drop in CSCs in nearly all participants who took doxycycline. Although participant numbers were very low, the results were highly significant, meaning that a clinical trial would be worth running.

[NEGATIVE] Effect of Antibiotic Use on Outcomes with Systemic Therapies in Metastatic Renal Cell Carcinoma (link)

The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated. Antibiotic use (n=709, 17%) adversely impacted OS in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines.

[NEGATIVE] Patients live longer if they do not take antibiotics in month before immunotherapy (link)

In lung cancer, where chest infections are more common, median survival was 2.5 months in those who had been on antibiotics before starting the immunotherapy drugs, known as checkpoint inhibitors, versus 26 months in those who had not. In melanoma it was 3.9 versus 14 months, and in other tumours five weeks versus 11 months.

Phase II study of interferon-alpha and doxycycline for advanced renal cell carcinoma, 2006

Objective: To assess the efficacy and toxicity of the combination of interferon-alpha and doxycycline in patients with metastatic renal cell carcinoma and to assess the effect of this treatment on serum vascular endothelial growth factor (VEGF) levels.

Patients and methods: Seventeen patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy greater than 4 months with radiologically evident advanced renal cell carcinoma were enrolled. Eight patients had prior nephrectomy and 10 patients were treated within 4 months of their diagnosis. Treatment consisted of interferon-alpha up to 9 million units subcutaneously three times per week and doxycycline 300 mg orally twice per day for weeks one and three of each four-week cycle. Toxicity was evaluated on a biweekly basis and response on a bimonthly basis. VEGF plasma levels were assessed monthly as a measure of potential antiangiogenic effect.

Results: No objective responses were seen. The mean duration of study was 2.6 cycles (range: 0.8-6.0 cycles). Three patients (17%) tolerated therapy and displayed stable disease for greater than four months. Five patients withdrew from study before the first response evaluation. Ten patients experienced grade 2 gastrointestinal toxicity requiring dose reduction of doxycycline. Eight patients experienced grade 2 fatigue requiring dose reduction of interferon. VEGF plasma levels were initially suppressed in patients who demonstrated progressive disease but not in patients with stable disease.

Conclusion: This regimen of doxycycline and interferon-alpha was not efficacious as treatment for renal cell carcinoma. Plasma VEGF levels were significantly decreased during the first two cycles of treatment, but this does not correlate with clinical outcome.