A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

Abstract

Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. "Mito-signatures") could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10-15 y) and billions in financial resources.

Keywords: Mito-signatures; Mito-therapeutics; Mitochondria; Mitoflavoscins; Mitoketoscins; Mitoriboscins; drug discovery; mito-biomarkers; oncology platform.

Figure 1.

Repurposing FDA-approved antibiotics for targeting mitochondria in CSCs. a) Doxycycline; b) Azithromycin; c) Pyrvinium (pamoate salt; not shown); d) Atovaquone; and e) Bedaquiline. Doxycycline and Azithromycin (a,b) are known to inhibit mitochondrial protein translation as an off-target side effect. They are used clinically as antibiotics to inhibit bacterial protein synthesis. Similarly, Pyrvinium pamoate and Atovaquone (c,d) are known to inhibit OXPHOS (related to mitochondrial complex II/III), as a side effect. Bedaquiline (e) was originally designed to inhibit the bacterial ATP-synthase, which is analogous to mitochondrial complex V. All of these FDA-approved drugs (a-e) have been shown to inhibit the anchorage-independent propagation of CSCs, by targeting mitochondrial function.

Figure 2.

Natural products used for targeting CSCs. a) Caffeic acid phenyl ester (CAPE); b) Vitamin C (Ascorbic acid); c) Actinonin and d) Silibinin. CAPE (from bee propolis) inhibits OXPHOS; Vitamin C blocks GAPDH (a glycolytic enzyme), which is directly upstream of mitochondrial metabolism; Actinonin inhibits the initiation of both bacterial and mitochondrial protein translation; Silibinin (from milk thistle) decreases glucose uptake, by targeting the GLUT family of transporters. These natural products all inhibit CSC expansion.

Figure 3.

Experimental compounds used for targeting CSCs. a) FK-866 (NAMPT inhibitor); b) Puromycin; and c) 2-Deoxy-glucose (2-DG). FK-866 potently inhibits the NAD(+) salvage pathway; Puromycin inhibits protein synthesis (both cellular and mitochondrial), as it resembles the structure of a tRNA; 2-DG is a modified form of glucose, in which the OH-group at the 2 position has been removed and replaced with a hydrogen atom. As a consequence, it cannot undergo complete glycolysis and competitively inhibits the pathway, blocking the formation of glucose-6-phosphate from glucose. These three experimental compounds all block CSC propagation, by interfering with energy metabolism.

Figure 4.

Mitoriboscins: Novel inhibitors for targeting the mitochondrial ribosome. Several examples of Mitoriboscins are illustrated. These compounds were identified by combining computational chemistry (in silico drug design), together with phenotypic library screening, to detect ATP depletion. The target used was the 3D structure of the large mitochondrial ribosome, as determined by cryo-EM (electron microscopy). For further details on these compounds, please see reference [23].

Figure 5.

Mitoketoscins: Therapeutics for targeting mitochondrial ketone metabolism. The pharmacaphore for Mitoketoscins is shown. These compounds were identified by combining computational chemistry (in silico drug design), together with phenotypic library screening, to detect ATP depletion. The targets used were the crystal structures of OXCT1 and ACAT1, mitochondrial enzymes involved in the conversion of serum ketone bodies back into Acetyl-CoA, for use in the TCA cycle.

Figure 6.

Mitoketoscins: Docking images with OXCT1 and ACAT1. (a) Compound 2 docking at the succinyl-CoA binding site of 3-oxoacid CoA-transferase 1 (OXCT1); (b) compound 8 docking at the CoA binding site of human acetyl-CoA acetyltransferase (ACAT1). Modified and reproduced from [24].

Figure 7.

Mitoflavoscins and Tri-phenyl-phosphonium (TPP). Upper, The structure of DPI (Diphenyleneiodonium chloride), a Mitoflavoscin, is shown. Lower, The structure of a representative TPP compoundis is shown.

Figure 8.

Components of Bergamot function as natural “statin-like” molecules. The chemical structures of a) Brutieridin and b) Melitidin are shown. The structure of c) mDIVI1 is also shown for comparison.

Figure 9.

Identifying mitochondrial-based companion diagnostics for more personalized cancer therapy. Briefly, mitochondrial markers could be used to stratify cancer patients into high-risk and low-risk groups, at diagnosis. Patients with high levels of mitochondrial markers (“bad prognosis”) could be treated with mitochondrial-based therapies, as an add-on to the standard of care, in order to effectively prevent tumor recurrence, metastasis and drug-resistance. Modified from [32,33].

Figure 10.

A short mitochondrial gene signature predicts tumor recurrence and distant metastasis, in high-risk breast cancer patients, receiving endocrine therapy. Note that high expression of this Mito-Signature predicts treatment failure on Tamoxifen (Tam). These represent ER-positive patients, with the luminal A sub-type of breast cancer, who showed local lymph node metastasis at diagnosis, with 10–15 y of follow-up data. RFS, recurrence-free survival; DMFS, distant metastasis-free survival. Reproduced with permission from [32].

Figure 11.

A short mitochondrial gene signature predicts drug-resistance and treatment failure in ovarian cancer patients. Note that high expression of this Mito-Signature predicts treatment failure on Platins and Taxol, in ovarian cancer patients. These patients with serous ovarian cancer had at least 5-years of follow-up data. Reproduced with permission from [33].

Figure 12.

A mitochondrial-based oncology platform for cancer therapy: MITO-ONC-RX. This oncology platform would consist of two basic components: i) Mito-therapeutics and ii) Mito-diagnostics. These components could then be tailored and optimized, for a given cancer type.