Cancer, while complex in its mechanisms and evolutionary background, can be pinpointed to a simple biological problem: the out of control growth and division of cells. Whether that be a car with a jammed gas pedal (oncogenes) or the loss of brakes (tumor-suppressor genes), cancer has fought off diverse therapies for centuries claiming a countless number of lives. Old remedies and “solutions” often caused more damage than help leaving many hopeless for a cure.
With the rise of scientific exploration and technological discoveries within the past 15 years, novel cancer treatments have been in development as a new way to treat patients that best suit them and their case. Rather than just killing the cells, these treatments often set out to minimize cell proliferation and specifically attack and single in on the cancerous cells (and even more specific molecules) while leaving the healthy cells intact. The two treatments I focused on were apoptosis inducers and hormone therapy. Since this is not a one size fits all approach, the outlook for these therapies seem promising but are always questioned based on cancers past and ability to render new and highly thought out therapies useless.
Apoptosis, also referred to as programmed cell death is a necessary function for the human body. It is vital in keeping the ratio of healthy cells balanced to allow a biological process to continue as usual. However, as a therapy, apoptosis can be induced into cancerous cells to give them the signal that they should no longer continue to operate and to die. These therapies, molecules, and treatments are based around apoptosis inducers. As previously mentioned, encouraging only the cancerous cells to divide via a natural process of apoptosis can greatly limit the number of cancerous cells in the body. The two apoptosis-inducing therapies that I will be discussing in depth is DNA cross-linking and inhibition of anti-apoptotic proteins.
DNA cross-linking is the process of the binding of two nucleotides on a DNA strand (Lawley and Phillips 1996). This can be either intrastrand (nucleotides on the same strand) or interstrand (nucleotides from both strands). When linkage forms it creates an “adduct”, which interferes with DNA replication which does not allow for transcription. Because transcription cannot occur, the cell signals for apoptosis because the mutated DNA cannot and should not be replicated. While this is not healthy for the human body to occur in normal functioning cells, targeting specific cancerous cells to undergo DNA cross-linking can naturally induce apoptosis in those cells, blocking proliferation.
While repair is possible, it is more common for the DNA polymerase to repair intrastrand linking then interstand linking. The reason for this is not 100% clear but scientists believe that DNA polymerase can keep up with correcting the errors produced from interstrand cross-linking as the repair pathways and amount of work needed are much less of a burden (Noll and Mason et al., 2006). This means that interstrand DNA cross-linking is much more deadly as the DNA polymerase cannot keep up with the errors and more cells accumulate in G2 and M phase leading to more apoptosis.
Carboplatin, commonly sold under the name ParaplatinⓇ is very similar to its derivative of cisplatin and is most commonly used for ovarian, lung, head, and neck cancer. Being an alkylating agent, carboplatin removes hydrogen atoms and substitutes them with an alkyl group (Brabec and Kasparkova, 2005). This creates adducts in the DNA and does not allow for transcription to occur, which is when apoptosis ensues.
Once carboplatin crosses the cell membrane, it becomes hydrolyzed, giving the molecule a positive charge which allows the platinum complex to react with other molecules (Mcwhinney et al., 2009). Once Carboplatin is able to interact with other molecules (such as nucleotides), it will bind to the DNA nucleotides forming adducts. These lesions (adducts) can be monoadducts (if bound to the end of a DNA strand) or intra/interchain diadducts. The adducts will negatively impact transduction which will trigger the apoptotic signaling pathway for the cell.
Although there is a diverse group of alkylating agents, platinum-based chemotherapy is the biggest obstacle physicians face. The reasons for this is not completely understood but there is sufficient evidence that some alkylating agents are stronger in combating cancer than others (Wernyj and Morin, 2004). Comparing this drug to another alkylating agent, cisplatin, there are benefits and drawbacks to both as well as times where utilization of one will lead to a better prognosis for the patient. As I hinted to earlier, the structures of both these compounds contain a platinum base attached to two thiol groups. The only difference is that cisplatin has a di-chloro leaving group while carboplatin contains a cyclobutane dicarboxylic acid leaving group. Based on simple organic chemistry, since the chlorines are better-leaving groups, cisplatin will be capable of forming interstrand DNA cross-linking which is more potent (Amptoulach et al., 2006).
Since carboplatin causes intrastrand DNA crosslinking 90% of the time, it is less potent and the body almost always becomes resistant to it (DNA polymerase out works carboplatin). However, since carboplatin is much less potent, it is more tolerable by more people and is often used over cisplatin as it will give the physicians a baseline of the patient's reaction to these drugs.
To conclude, while the potency of these two drugs varies, there is not necessarily a benefit to using one over the other as there has been no clear evidence to show that one drug greatly increase the progressive as well as reduces remission.
The second apoptotic inducing therapy I researched was the inhibition of anti-apoptotic proteins. Apoptotic proteins are proteins that aid in the process of apoptosis, these are pro-apoptotic. There are also proteins that do not allow for apoptosis and keep the cell alive which are called anti-apoptotic proteins, as they are pro-life cells. Targeting cancerous cell proteins that inhibit cell death will instead encourage cells to die and will stop cancer cell proliferation In specific, by targeting certain members of the Bcl-2 family of proteins allowed for the inhibition of pro-survival proteins
The Bcl-2 family of proteins is often referred to as the “gatekeepers” of apoptosis in cells for their extensive roles in cell death. These proteins are divided based on common homology ranging on domains 1, 2, 3, and 4 shared between them, it is their homology that categorizes them into their functioning groups. The family can be broken into three main categories: those who share homology on all four domains (BH1-BH4) are categorized as anti-apoptotic proteins such as Bcl-2 and Bcl-XL, those who share homology on domains BH1-BH3 are multi-domain effector pro-apoptotic proteins such as Bax and Bak, and lastly BH3 only proteins such as Bid and Bim. BH3 only proteins regulate the pro and anti-apoptotic proteins (Meier et al., 200). They are also “activator” proteins, they receive signals from a cell under stress who then pass the message onto effector proteins like BAX and BAK that actually carry out apoptosis (Strasser et al., 2000).
When a cell receives some sort of stress such as chemotherapy or severe DNA damage (such that carboplatin causes), the intrinsic apoptotic pathway is activated. In this pathway, pro-apoptotic proteins such as Bax is activated and is located into the mitochondrial membrane. When this happens, Bax is inserted onto the outer mitochondrial membrane where pores form on the mitochondria (Abdelawahid et al., 2010). Thes permeabilization of the membrane releases cytochrome c into the cytosol. In the cytoplasm, the apoptosome is formed when cytochrome c, Apaf-1, and procaspase-9 bind together. Caspase 9 is vital as it is the initiator caspase for the intrinsic pathway of apoptosis as it sends signals to executioner caspases 7 and or 3 to cleave the target molecule and carry out apoptosis (Danial and Korsmeyer, 2004).