Doxycycline treatment for early breast cancer

This article is part of the 2019 Oncology Special IssueJournal of naturopathy. Read the full issue here.

Relation

Scatena C, Roncella M, Di Paolo A, et al. Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early-stage breast cancer patients: a pilot clinical study. (Link removed). 2018;8:452.

Objective

This pilot clinical trial examined whether short-term preoperative treatment with doxycycline reduced cancer stem cell (CSC) activity in breast cancer patients.

Participant

A total of 15 women with early-stage breast cancer took part. Nine patients received doxycycline for 14 days between breast biopsy and lumpectomy. Six post-lumpectomy samples were used as controls (no treatment). Controls were selected from women well matched for age and clinical characteristics.

In the doxycycline treatment group, patient age at diagnosis ranged from 42 to 65 years, tumor size varied from 10 to 30 mm, and 7 of 9 patients were estrogen receptor (ER) positive (ER+), with 6 of the luminal A subtype and one of the luminal B subtype. Six of 9 patients were grade 2 or intermediate in Ki-67. In addition, 2 patients were of the HER2(+) subtype.

intervention

The women received oral doxycycline 200 mg per day for 14 days before surgery, using a breast biopsy as baseline.

Target parameters

Testing was performed on each participant's biopsy and postresection samples, and comparisons were made between measurements for each sample. All samples were tested for known biomarkers of stemness (CD44, ALDH1); mitochondria (TOMM20); cell proliferation (Ki-67, p27); apoptosis (cleaved caspase-3); and neoangiogenesis (CD31). Changes from baseline to posttreatment were assessed using MedCalc 12 (unpaired t test) and ANOVA.

Key insights

Post-doxycycline tumor samples showed a statistically significant decrease in the stemness marker CD44 (P<0.005) compared to tumor samples before doxycycline. CD44 levels were reduced by 17.65% to 66.67% in 8 of 9 doxycycline-treated patients. One patient showed a 15% increase in CD44. Overall, this corresponds to a positive response rate of almost 90%. Similar results were obtained for ALDH1, another marker of stemness.

From the time of biopsy to resection, there were no changes in any of the biomarkers measured in the control group samples, so the biopsy itself is unlikely to have any effect on the measurement of stemness.

Practice implications

Cancer stem cells are known to confer resistance to treatment and potentially give rise to the tumor itself. As Dawood and colleagues summarized in a 2014 review on the topic:

"Cancer stem cells have been identified in a number of solid tumors, including breast cancer, brain tumors, lung cancer, colon cancer and melanoma. Cancer stem cells have the ability to renew themselves, produce progeny that are different from themselves, and use common signaling pathways. Cancer stem cells can be the source of all tumor cells present in a malignant tumor, the reason for resistance to the chemotherapy drug used to treat the malignant tumor and the source of cells that lead to distant metastases.”¹

To understand the implications of these results, we should look at some of the previous work these researchers published prior to this study.

In 2015, Michael Lisanti reported that antibiotics that target mitochondria can eradicate cancer stem cells in several types of cancer. In other words, it is possible to “treat cancer like an infectious disease.”²They had first examined cancer stem cells from multiple tumor types and “identified a conserved phenotypic weakness – a strict dependence on mitochondrial biogenesis for clonal expansion and survival of cancer stem cells.”

Simply adding vitamin C and berberine during doxycycline treatment could enhance anticancer effects.

Their analysis revealed that stem cell mitochondria could be the Achilles heel of stem cells. Aware that several classes of antibiotics inhibit mitochondrial biogenesis, they next identified a list of drugs that could eradicate cancer stem cells in 12 different cancer cell lines and across 8 different tumor types (i.e. breast, ductal carcinoma in situ, ovary, prostate, lung, pancreas, melanoma, glioblastoma).²That same year, these researchers identified doxycycline as the drug of choice for targeting cancer stem cell mitochondria.³

The US Food and Drug Administration first approved doxycycline as a broad-spectrum antibiotic in 1967. The standard dose is 200 mg/day. Remember that in an evolutionary sense, mitochondria are descendants of bacteria and remain sensitive to the antibiotics that are more commonly used to inhibit bacterial growth.⁴

Doxycycline is already used to treat infections in cancer patients, and there are case reports of unexpected remissions, particularly in lymphoma.^5.6

In April 2017, Zhang et al. the effect of doxycycline in inhibiting the transition steps of stem cell phenotypes to breast cancer.⁷

In June 2017, this research took a turn that many of us will find fascinating: Lisantis' group reported that the effects of doxycycline are optimized in combination with vitamin C and berberine in vitro. (The breast cancer patients in the study reviewed here received only doxycycline. Vitamin C and berberine were not included in the study protocol.) Doxycycline is so effective at suppressing cancer stem cell populations that it creates high selection pressure that synchronizes the surviving cancer cell population to a predominantly glycolytic one Phenotype, resulting in metabolic inflexibility. They identified 2 natural products (ie, vitamin C, berberine) and 6 clinically approved drugs (ie, atovaquone, irinotecan, sorafenib, niclosamide, chloroquine, stiripentol) that target the doxycycline-resistant CSC population. This combination strategy eliminates surviving cancer stem cells, which the researchers say provides “a simple pragmatic solution to the possible development of doxycycline resistance in cancer cells.”⁸This previous in vitro work suggested that doxycycline not only inhibits CSCs but may work best when combined with agents that exploit metabolic inflexibility, such as vitamin C and berberine.⁸

In light of these previous publications, the small clinical trial discussed in this review has been published. This pilot study suggests that doxycycline at commonly prescribed doses may reduce the "strains" of tumors in women with breast cancer.

These results suggest, but do not prove, effectiveness. The observed significant decrease in stemness is not evidence that doxycycline reduces the risk of recurrence or slow progression of advanced cancer in the real world. However, given the safety profile of doxycycline, it is tempting to use this treatment strategy before definitive evidence is published. Of note, an April 2019 publication suggested that the addition of azithromycin could further improve the effectiveness of a combination of doxycycline and vitamin C.⁹

These publications suggest some obvious implications. Patients occasionally take doxycycline to treat infections. This could be a useful opportunity. Simply adding vitamin C and berberine during doxycycline treatment could enhance anticancer effects. There is no published evidence that this reduces the risk of cancer or its recurrence, but could it do harm?

Such prophylaxis could be particularly useful in patients previously treated for cancer whose recurrences we believe are caused by cancer stem cells. Glioblastoma and ovarian cancer come to mind.

In recent years, some practitioners have promoted treatment strategies that are the exact opposite of Lisanti's approach. The thinking is that mitochondrial damage is responsible for cancer progression and therefore supplements selected to repair mitochondrial damage should be beneficial.¹⁰These two approaches are so directly opposed to each other that one might rightly assume that both ideas cannot be true. It is possible that preventing cancer involves preserving mitochondria, whereas the presence of established cancer should be viewed as a distinctly different condition for the cells and their mitochondria.¹¹

An August 2019 article identified oxidative phosphorylation itself as a potential therapeutic target for cancer therapy.¹²

Based on published evidence available at this time, Lisanti's argument for targeting mitochondrial biogenesis is compelling once cancer stem cells are present. It is certainly better proven than any suggestion that nutrition and promotion of mitochondrial biogenesis is beneficial, even if the latter seems more philosophically congruentcompared to medicatrix naturae.